Continuous arycyclic compound

ABSTRACT

This is to provide a continuous arycyclic compound having a DGAT1 inhibitory activity, and useful for prophylaxis and/or treatment of obesity or hyperlipidemia caused by obesity, hypertriglyceridemia, lipid metabolism disorder, fatty liver, hypertension, arteriosclerosis, diabetes, etc., as well as to provide a DGAT1 inhibitor comprising the continuous arycyclic compound or a pharmaceutically acceptable salt thereof as an effective ingredient. Disclosed is the continuous arycyclic compound is represented by the formula: wherein the substituents in the formula are the same as defined in the specification, or a pharmaceutically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of copending application Ser. No.13/994,543, filed on Jun. 14, 2013, which was filed as the NationalPhase of PCT/JP2011/079958 filed on Dec. 16, 2011, which claims priorityunder 35 U.S.C. §119(e) to U.S. Provisional Application No. 61/424,365filed on Dec. 17, 2010, all of which are hereby expressly incorporatedby reference into the present application.

TECHNICAL FIELD

The present invention relates to a continuous arycyclic compound or apharmaceutically acceptable salt thereof having acyl coenzyme A:diacylglycerol acyltransferase (DGAT) 1 inhibitory activity.

BACKGROUND ART

Obesity is a state in which fat is excessively accumulated in a body(Non-Patent Literature 1), hyperlipidemia, hypertriglyceridemia (TG),and causes lifestyle diseases such as lipid metabolism disorder, fattyliver, diabetes, hypertension, arteriosclerosis, etc.; cerebrovasculardisease, coronary heart disease, dyspnoea, lumbago, knee osteoarthritis,etc., and among obesity, those involving these diseases, or having apossibility of causing these diseases in the future are defined to beobesity and handled as one disease.

DGAT is an enzyme catalyzing a reaction from diacylglycerol to TG whichis the final stage of TG synthesis, and it has been known that two kindsof subtypes of DGAT1 and DGAT2 exist in DGAT. Of these, DGAT1 has beenknown to exist in liver, skeletal muscle, adipocytes, etc., and toparticipate in TG synthesis in the respective tissues (Non-PatentLiterature 2).

Also, at the time of TG absorption at the small intestine, TG isdecomposed to fatty acid and monoacyl glycerol by pancreatic lipase inlumen of the small intestine, then, took into small intestinalepithelial cells, and absorbed after resynthesis to TG in the epithelialcells. It has also been known that DGAT1 is participated in TGresynthesis at the final stage in the small intestinal epithelial cells(Non-Patent Literature 3).

Thus, a drug which inhibits an action of DGAT1 can inhibit the finalstage of TG synthesis so that it can not only inhibit TG synthesis inadipocyte, liver, etc., but also inhibit TG resynthesis in the smallintestine, whereby it is expected to inhibit TG absorption in the smallintestine and the diseased state of obesity can be improved (Non-PatentLiterature 4).

Further, a thesis that accumulation of TG in liver, skeletal muscle,etc. (ectopic adiposity) is a cause of insulin resistance of type 2diabetes accompanied by obesity has widely been accepted, so that it hasbeen said that a drug which inhibits an action of DGAT1 is expected toimprove insulin sensitivity and to have a treatment effect on type 2diabetes by reducing ectopic adiposity (Non-Patent Literature 4). Also,it has been reported that improvement in insulin sensitivity can beadmitted in a mouse in which DGAT1 is knocked out by gene manipulation(DGAT1 knockout mouse) as compared with that of a wild type mouse(Non-Patent Literature 5). Recently, it has also been reported that thecompound which inhibits the action of DGAT1 stimulates actions ofglucagon-like peptide-1 (GLP-1) and a protein which causes loss ofappetite (anorexia) (Non-Patent Literature 6).

As a compound having a continuous arycyclic structure, the followinghave been known. For example, Patent Literature 1 discloses(2S)-2-[4′-(1-benzyl-1H-benzimidazol-2-yl)-biphenyl-4-yloxy]-3-phenyl-propionicacid (Example 70), etc., as a compound which inhibits Protein-tyrosinephosphatases (PTPases), and useful for the treatment of obesity, glucoseintolerance, diabetes, hypertension, and insulin tolerance accompaniedby ischemic disease.

Patent Literature 2 discloses, as a compound having Protein-tyrosinephosphatase-1B (PTP-1B) inhibitory activity useful for the treatment oftype 2 diabetes,2-benzyl-4-[4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yl]-4-oxo-butyricacid (Example 1),({4′-(3-benzylamino)imidazo[1,2-a]pyridin-2-yl)biphenyl-4-yl}oxy)(phenyl)aceticacid, {[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid(Example 3), etc.

Patent Literature 3, Patent Literature 4 and Patent Literature 5disclose compounds having structures in which biphenyl having aninhibitory activity against factor VIIa, factor IXa, factor Xa andfactor XIa, and a nitrogen-containing fused hetero ring are bonded.However, their chemical structures are limited to the structures inwhich the nitrogen-containing fused hetero ring is bonded to 3-positionof the biphenyl.

Patent Literature 6 discloses2-[[2′-(5-phenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]acetic acid(Example 46), etc. as a compound having a treatment effect on obesityand diabetes by inhibiting adipocyte-type fatty acid binding protein(aP2).

Non-Patent Literature 7 reports2-[[2′-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]aceticacid,2-[[2′-(4,5-diphenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]aceticacid, etc. as a compound binding to adipocyte-type fatty acid bindingprotein (aFABP).

PRIOR ART LITERATURES Patent Literatures

-   [Patent Literature 1] WO99/58518A-   [Patent Literature 2] WO2004/99168A-   [Patent Literature 3] WO2003/6670A-   [Patent Literature 4] WO2003/6011A-   [Patent Literature 5] US 2003/0114457A-   [Patent Literature 6] WO00/59506A

Non-Patent Literatures

-   [Non-Patent Literature 1] Nanzando Co., Ltd., Medical Dictionary    (19th Edition) p. 2113, 2006-   [Non-Patent Literature 2] Proc. Natl. Acad. Sci. USA vol. 95, p.    13018, 1998-   [Non-Patent Literature 3] J. Biol. Chem. Vol. 278, p. 18532, 2003-   [Non-Patent Literature 4] Arterioscler. Thromb. Vasc. Biol. Vol.    25, p. 482, 2005-   [Non-Patent Literature 5] The Journal of Clinical Investigation,    109(8) 1049-1055, 2002-   [Non-Patent Literature 6] American Chemical Society National Meeting    Abst. MEDI 315, 2010-   [Non-Patent Literature 7] Bioorganic & Medicinal Chemistry Letters    17(12) 3511-3515, 2007

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a continuous arycycliccompound or a pharmaceutically acceptable salt thereof having a DGAT1inhibitory activity, and a DGAT1 inhibitor useful for prophylaxis and/ortreatment of obesity or hyperlipidemia caused by obesity,hypertriglyceridemia, lipid metabolism disorder, fatty liver,hypertension, arteriosclerosis, diabetes, etc. Also, another object ofthe same is to provide a DGAT1 inhibitor comprising a continuousarycyclic compound or a pharmaceutically acceptable salt thereof as aneffective ingredient.

Means to Solve the Problems

The present inventors have carried out intensive studies to solve theabove-mentioned problems, and as a result, they have found that thecontinuous arycyclic compound or a pharmaceutically acceptable saltthereof of the present invention has excellent DGAT1 inhibitory activitywhereby the present invention has accomplished. That is, the presentinvention is as follows.

1. A continuous arycyclic compound represented by the formula:

{wherein Alk represents a linear C₁₋₆ alkylene group, branched C₁₋₆alkylene group, or C₁₋₆ alkylene group having a ring structure (a partof the carbon atoms constituting the ring structure may be optionallysubstituted by an oxygen atom, a nitrogen atom or a sulfur atom.),

in Ring X,

X¹ represents N or CR^(X1),X² represents N or CR^(X2),X³ represents N or CR^(X3),X⁴ represents N or CR^(X4),R^(X1), R^(X2), R^(X3), and R^(X4) each independently represent ahydrogen atom; a linear or branched C₁₋₆ alkyl group which may besubstituted by a halogen atom(s); a C₃₋₇ alkyl group having a ringstructure which may be substituted by a halogen atom(s); a linear orbranched C₁₋₆ alkoxy group; a halogen atom or cyano group,

in Ring Y,

Y¹ represents N or CR^(Y1),Y² represents N or CR^(Y2),Y³ represents N or CR^(Y3),Y⁴ represents N or CR^(Y4),R^(Y1), R^(Y2), R^(Y3) and R^(Y4) each independently represent ahydrogen atom; a linear or branched C₁₋₆ alkyl group which may besubstituted by a halogen atom(s); a C₃₋₇ alkyl group having a ringstructure which may be substituted by a halogen atom(s); a linear orbranched C₁₋₆ alkoxy group; a halogen atom or cyano group,

in Ring Z,

R^(Z) represents a linear or branched C₁₋₆ alkyl group which may besubstituted by a halogen atom(s) or C₃₋₇ alkyl group having a ringstructure which may be substituted by a halogen atom(s).}or a pharmaceutically acceptable salt thereof.2. The continuous arycyclic compound or a pharmaceutically acceptablesalt thereof described in the above item 1, wherein Ring X has astructure represented by any one of the following formulae:

wherein R^(X1) to R^(X4) have the same meanings as defined above,

Ring Y has a structure represented by any one of the following formulae:

wherein R^(Y1) to R^(Y4) have the same meanings as defined above.

3. The continuous arycyclic compound or a pharmaceutically acceptablesalt thereof described in the above item 2, wherein Ring X has astructure represented by any one of the following formulae:

wherein R^(X1) to R^(X4) have the same meanings as defined above,

Ring Y has a structure represented by any one of the following formulae:

wherein R^(Y1) to R^(Y4) have the same meanings as defined above.

It is preferred that Ring X has a structure represented by any one ofthe following formulae:

wherein R^(X1) to R^(X4) have the same meanings as defined above,

Ring Y has a structure represented by any one of the following formulae:

wherein R^(Y1) to R^(Y4) have the same meanings as defined above.

It is more preferred that Ring X and Ring Y have structures representedby any one of the following formulae:

wherein R^(X1) to R^(X4) and R^(Y1) to R^(Y4) have the same meanings asdefined above.

4. The continuous arycyclic compound or a pharmaceutically acceptablesalt thereof described in the above item 3, wherein R^(Z) is a linear orbranched C₁₋₆ alkyl group which is substituted by a halogen atom(s), ora C₃₋₇ alkyl group having a ring structure which may be substituted by ahalogen atom(s).5. The continuous arycyclic compound or a pharmaceutically acceptablesalt thereof described in the above item 4, wherein Alk is a branchedC₂₋₄ alkylene group.6. A continuous arycyclic compound which is any one of the followingcompounds:

-   2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-propanoic    acid;-   2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoic    acid;-   2,2-dimethyl-3-(4-{4-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}-phenoxy)propanoic    acid;-   2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoic    acid;-   2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)-propanoic    acid;-   1-[(3-methyl-4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-methyl]cyclobutanecarboxylic    acid;-   3-(4-{5-[5-(3,3-difluorocyclobutyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoic    acid;-   2,2-dimethyl-3-({4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoic    acid;-   2,2-dimethyl-3-({4′-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2,3′-bipyridin-6′-yl}oxy)propanoic    acid;-   2,2-dimethyl-3-[(4-methyl-5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]propanoic    acid;-   2,2-dimethyl-3-[(6-methyl-5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]propanoic    acid;-   3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid;-   2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]-propanoic    acid;-   2,2-dimethyl-3-[(4-methyl-5-{3-methyl-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]-phenyl}pyridin-2-yl)oxy]propanoic    acid;-   3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid;-   2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]-propanoic    acid;-   3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid;-   3-{[5-(3-fluoro-4-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}phenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoic    acid;-   2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoic    acid;-   3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-fluorophenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid;-   1-[({4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic    acid;-   1-{[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic    acid;-   1-[({5′-chloro-4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic    acid;-   1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic    acid;-   1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic    acid,    or a pharmaceutically acceptable salt thereof.    7. An acyl coenzyme A: diacylglycerol acyltransferase (DGAT) 1    inhibitor comprising the continuous arycyclic compound or a    pharmaceutically acceptable salt thereof described in any one of the    above items 1 to 6 as an effective ingredient.    8. The DGAT1 inhibitor described in the above item 7 which is a    prophylactic or treatment agent of obesity.    9. The DGAT1 inhibitor described in the above item 8 which is a    prophylactic or treatment agent of hyperlipidemia,    hypertriglyceridemia, lipid metabolism disorder or fatty liver.    10. The DGAT1 inhibitor described in the above item 7 which is a    prophylactic or treatment agent of type 2 diabetes, diabetic    complication (including diabetic peripheral neuropathy, diabetic    nephropathy, diabetic retinopathy and diabetic macrovascular    disease), arteriosclerosis, hypertension, cerebrovascular disease,    coronary heart disease, dyspnoea, lumbago or knee osteoarthritis.    11. The DGAT1 inhibitor described in the above item 10 which is a    prophylactic or treatment agent of type 2 diabetes or diabetic    complication.    12. Use of the continuous arycyclic compound or a pharmaceutically    acceptable salt thereof described in any one of the above items 1 to    6 for the prophylaxis or treatment of hyperlipidemia,    hypertriglyceridemia, lipid metabolism disorder, fatty liver; type 2    diabetes, diabetic complication (including diabetic peripheral    neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic    macrovascular disease), arteriosclerosis, hypertension,    cerebrovascular disease, coronary heart disease, dyspnoea, lumbago    or knee osteoarthritis.    13. A prophylaxis or treatment method of hyperlipidemia,    hypertriglyceridemia, lipid metabolism disorder, fatty liver; type 2    diabetes, diabetic complication (including diabetic peripheral    neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic    macrovascular disease), arteriosclerosis, hypertension,    cerebrovascular disease, coronary heart disease, dyspnoea, lumbago    or knee osteoarthritis which comprises administering therapeutically    effective amount of the continuous arycyclic compound or a    pharmaceutically acceptable salt thereof described in any one of the    above items 1 to 6 to a patient.

In the above descriptions, the linear or branched C₁₋₆ alkylene groupincludes a linear C₁₋₆ alkylene group and a branched C₂₋₆ alkylenegroup, and specifically mentioned the following alkylene group.

-   1) —CH₂—;-   2) —CH₂CH₂—, —CH(CH₃)—;-   3) —CH₂CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —C(CH₃)₂—, —CH(C₂H₅)—;-   4) —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—,    —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—, —CH(C₂H₅)CH₂—,    —CH₂CH(C₂H₅)—, —CH(n-C₃H₇)—, —CH(i-C₃H₇)—;-   5) —CH₂CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—,    —CH₂CH₂CH(CH₃)CH₂—, —CH₂CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,    —CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—, —CH(CH₃)CH(CH₃)CH₂—,    —CH(CH₃)CH₂CH(CH₃)—, —CH₂CH(CH₃)CH(CH₃)—, —CH(C₂H₅)CH₂CH₂—,    —CH₂CH(C₂H₅)CH₂—, —CH₂CH₂CH(C₂H₅)—, —C(CH₃)₂CH(CH₃)—,    —CH(CH₃)C(CH₃)₂—, —CH(C₂H₅)CH(CH₃)—, —CH(CH₃)CH(C₂H₅)—,    —CH(n-C₃H₇)CH₂—, —CH(i-C₃H₇)CH₂—, —CH₂CH(n-C₃H₇)—, —CH₂CH(i-C₃H₇)—,    —CH(n-C₄H₉)—, —CH(i-C₄H₉)—, —CH(sec-C₄H₉)— or —CH(t-C₄H₉)—;-   6) —CH₂CH₂CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂CH₂CH₂—,    —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₃)CH₂—,    —CH₂CH₂CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂CH₂—, —CH₂C(CH₃)₂CH₂CH₂—,    —CH₂CH₂C(CH₃)₂CH₂—, —CH₂CH₂CH₂C(CH₃)₂—, —CH(CH₃)CH(CH₃)CH₂CH₂—,    —CH(CH₃)CH₂CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂CH(CH₃)—,    —CH₂CH(CH₃)CH(CH₃)CH₂—, —CH₂CH(CH₃)CH₂CH(CH₃)—,    —CH₂CH₂CH(CH₃)CH(CH₃)—, —CH(C₂H₅)CH₂CH₂CH₂—, —CH₂CH(C₂H₅)CH₂CH₂—,    —CH₂CH₂CH(C₂H₅)CH₂—, —CH₂CH₂CH₂CH(C₂H₅)—, —CH(CH₃)CH(CH₃)CH(CH₃)—,    —CH(C₂H₅)CH(CH₃)CH₂—, —CH(C₂H₅)CH₂CH(CH₃)—, —CH(CH₃)CH(C₂H₅)CH₂—,    —CH₂CH(C₂H₅)CH(CH₃)—, —CH(CH₃)CH₂CH(C₂H₅)—, —CH₂CH(CH₃)CH(C₂H₅)—.    Of these alkylene groups, a branched C₂₋₆ alkylene group is    preferred, a branched C₂₋₄ alkylene group is more preferred, and    —C(CH₃)₂— is particularly preferred.

In the above-mentioned descriptions, the “C₁₋₆ alkylene group having aring structure” includes the structure represented by the followingformula:

(wherein D represents CH₂, NH, O, or S, p is an integer of 1 to 2, and qis an integer of 0 to 2.)more specifically, the following structures are mentioned.

The linear and branched C₁₋₆ alkyl group and the linear and branchedC₁₋₆ alkoxy group may be mentioned an alkyl group and an alkoxy groupcorresponding to the above-mentioned linear and branched alkylenegroups. The alkyl group is preferably a linear C₁₋₆ alkyl group, morepreferably a linear C₁₋₄ alkyl group, particularly preferably methylgroup and ethyl group. Also, the alkoxy group is preferably a linearC₁₋₆ alkoxy group, more preferably a linear C₁₋₄ alkoxy group,particularly preferably methoxy group and ethoxy group.

The C₃₋₇ alkyl group having a ring structure includes those comprising acycloalkyl ring alone, and those comprising a cycloalkyl ring and alinear alkyl group in combination, and specifically mentioned thefollowing.

3)

Among the C₃₋₆ alkyl group having a ring structure of R^(X1), R^(X2),R^(X3), R^(X4), R^(Y1), R^(Y2), R^(Y3), and R^(Y4), a C₃₋₅ alkyl grouphaving a ring structure is more preferred, and particularly preferablythe following cyclopropylmethyl group.

Among the C₃₋₆ alkyl group having a ring structure of R^(Z), a C₃₋₅alkyl group having a ring structure is preferred, and particularlypreferably the following:

The halogen atom which may be substituted to the linear or branched C₁₋₆alkyl group or the C₃₋₇ alkyl group having a ring structure may bementioned a fluorine atom, a chlorine atom, a bromine atom or an iodineatom, and a fluorine atom is preferred.

The linear or branched C₁₋₆ alkyl group or the C₃₋₇ alkyl group having aring structure may be substituted by 1 to 5 halogen atom(s), and morepreferably may be substituted by 2 or 3 halogen atoms.

The continuous arycyclic compound (I) of the present invention has astructure in which Ring X and Ring Y are both 6-membered aromatic rings,and they are bonded at the 1,4-positions, so that it has a linearstructure as a whole molecule, and has a novel structure in which it hasan acidic carboxyl group at one end of the molecule, and has a basicimidazole ring at the other end of the same.

In the continuous arycyclic compound (I) of the present invention, atautomerism shown by the following formula is caused by transfer of ahydrogen ion on Ring Z, and even when the continuous arycyclic compound(I) of the present invention is shown by either one of the chemicalstructures, it includes either of the tautomers and a mixture thereof.

The continuous arycyclic compound (I) of the present invention has abasic group and a acidic group in the molecule, and the pharmaceuticallyacceptable salt thereof may be mentioned an acid addition salt (forexample, an inorganic acid salt such as a hydrochloride, a sulfate, aphosphate, a hydrobromide, etc., an organic acid salt such as anacetate, a fumarate, a maleate, an oxalate, a citrate, amethanesulfonate, a benzenesulfonate, toluenesulfonate, etc.) and a saltwith a base (for example, an alkali metal salt such as a sodium salt,potassium salt, etc., an alkaline earth metal salt such as a calciumsalt, etc., an organic base salt such as a triethylamine salt, etc., anamino acid salt such as a lysine salt, etc.).

Effects of the Invention

The continuous arycyclic compound (I) or a pharmaceutically acceptablesalt thereof of the present invention has excellent DGAT1 inhibitoryactivity, and useful as a medicine for prophylaxis and/or treatment ofthe following mentioned diseases of a warm blooded animals (preferablymammals including human).

(1) Diseases relating to fat accumulation (adiposity): hyperlipidemia,hypertriglyceridemia, lipid metabolism disorder, fatty liver, etc.(2) Diseases considered to be caused by fat accumulation (adiposity):type 2 diabetes, diabetic complication (including diabetic peripheralneuropathy, diabetic nephropathy, diabetic retinopathy and diabeticmacrovascular disease); arteriosclerosis, hypertension, cerebrovasculardisease, coronary heart disease; dyspnoea, lumbago, knee osteoarthritis,etc.

Also, the continuous arycyclic compound (I) or a pharmaceuticallyacceptable salt thereof of the present invention has a GLP-1secretagogue action based on the DGAT1 inhibitory activity, so that itcan be expected to have an insulin secretomotory action and pancreasprotecting action.

BEST MODE TO CARRY OUT THE INVENTION

The continuous arycyclic compound (I) of the present invention can beprepared according to the methods mentioned below.

(Method A)

(in the above-mentioned formulae, HAL₁, HAL₂ and HAL₃ each represent ahalogen atom, PROT₁ represents a protective group for a polar functionalgroup, PROT₂ represents a protective group for a hydroxyl group, PROT₃represents a protective group for a carboxyl group, and the othersymbols have the same meanings as defined above.)

(Method B)

(in the above-mentioned reaction formula, HAL₄ and HAL₅ each represent ahalogen atom, and the other symbols have the same meanings as definedabove.)

(Method C)

(in the above-mentioned reaction formula, the symbols have the samemeanings as defined above.)

(Method D)

(in the above-mentioned reaction formula, HAL₆ represents a halogenatom, PROT₄ represents a protective group for a carboxyl group, and theother symbols have the same meanings as defined above.)

(Method A) Step 1A

As Compound (II) and Compound (III), those in which HAL₁, HAL₂ and HAL₃are a chlorine atom, bromine atom or iodine atom can be used.

A ring-forming reaction of Compound (II) or a salt thereof and Compound(III) or a salt thereof and ammonia can be carried out, for example,according to the description of J. J. Baldwin et al., Journal ofMedicinal Chemistry, 29(6), 1065-1080, 1986, etc., in a suitablesolvent, in the presence of a base. As the solvent, water, and analcoholic solvent such as methanol, ethanol, etc. can be used alone orin admixture. The base can be optionally used an organic base such as analkali metal acetate (for example, sodium acetate), etc. The reactioncan be carried out firstly heating Compound (III) or a salt thereof at90 to 100° C. in the presence of a base, and after cooling, addingCompound (II) or a salt thereof and ammonia to the mixture, underice-cooling to 50° C., preferably at room temperature to 40° C.

Step 2A

Compound (V) may be mentioned that in which PROT₁ is, for example, aprotective group for the polar functional group which is generally usedin the organic synthetic chemistry as described in “Protective Groups inOrganic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons1991, and such a protective group may be mentioned, for example,2-(trimethylsilyl)ethoxymethyl group, t-butoxycarbonyl group,benzyloxycarbonyl group, benzyl group, 9-fluorenylmethoxycarbonyl group,2,2,2-trichloroethoxycarbonyl group, etc.

The reaction of Compound (IV) formed in Step 1A with Compound (V) can becarried out depending on the kind of a protective group according to theconventional method of introducing the protective group to the polarfunctional group. For example, when PROT₁ is2-(trimethylsilyl)ethoxymethyl group or benzyl group, it can be carriedout in the presence of a strong base in an aprotic polar solvent. Theaprotic polar solvent may be suitably used, for example,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.,and the strong base may be suitably used, for example, an alkali metalhydride (sodium hydride, lithium hydride) or an alkali metal carbonate(potassium carbonate). The reaction can be carried out at −20 to 50° C.,preferably under ice-cooling to room temperature.

Step 3A

Compound (VII) may be mentioned that in which PROT₂ is, for example, aprotective group for the hydroxyl group which is generally used in theorganic synthetic chemistry as described in “Protective Groups inOrganic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons1991, and such a protective group may be mentioned, for example, benzylgroup, trimethylsilyl group, t-butyldimethylsilyl group, etc.

The coupling reaction of Compound (VI) or a salt thereof formed in Step2A and Compound (VII) or a salt thereof can be carried out, for example,according to the method described in Advanced Organic Chemistry Part B(F. A. Carey & R. J. Sundberg, Springer), etc., in the presence of apalladium catalyst and a base in a suitable solvent. The —B(OH)₂ portionof Compound (VII) may be protected, if necessary, and, for example, the—B(OH)₂ portion may form 4,4,5,5-tetramethyl-1, 3-dioxaboran-2-yl groupwith the protective group. The solvent may be used water, an amidesolvent such as N,N-dimethylformamide, etc., an ether solvent such astetrahydrofuran, 1,4-dioxane, dimethoxyethane, etc, and toluene, etc.,singly or in combination of admixture thereof. The palladium catalystmay be used palladium chloride, palladium acetate,tetrakis(triphenylphosphine) palladium, etc., and the base may be usedan alkali metal base such as sodium carbonate, potassium carbonate,potassium phosphate, sodium hydroxide, etc., and cesium carbonate, etc.If necessary, a ligand such as 1,1′-bis(diphenylphosphino)ferrocene and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, etc., may be used. Thereaction can be carried out at room temperature to 150° C., preferablyat 60 to 120° C.

Step 4A

The reaction of removing the protective group (PROT₂) from Compound(VIII) formed in Step 3A can be carried out by the deprotecting methodof the protective group for the hydroxyl group which is generally usedin the organic synthetic chemistry as described in “Protective Groups inOrganic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons1991, and optimum method can be optionally selected depending on thekind of the protective group. For example, when PROT₂ is benzyl group,removal of the protective group can be carried out in the presence of apalladium catalyst such as palladium hydroxide, palladium carbon, etc.,in an alcohol solvent such as methanol, ethanol, etc., or an ethersolvent such as tetrahydrofuran, 1,4-dioxane, etc., under hydrogenatmosphere.

Step 5A

Compound (Xa) and (Xb) may be mentioned those in which PROT₃ is, forexample, a protective group for the carboxyl group which is generallyused in the organic synthetic chemistry as described in “ProtectiveGroups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley andSons 1991, and such a protective group may be mentioned, for example, analkyl group such as methyl group, ethyl group, etc., benzyl group,t-butyl group, allyl group, etc.

The dehydration reaction of Compound (IX) or a salt thereof formed inStep 4A and Compound (Xa) or a salt thereof can be carried out, forexample, according to the method described in Advanced Organic ChemistryPart B (F. A. Carey & R. J. Sundberg, Springer), Okuda, M.; Tomioka, K.;Tetrahedron Lett [TELEAY] 1994, 35 (26), 4585-4586, etc., in thepresence of a dehydrating agent in a suitable solvent. The solvent maybe used an ether solvent such as tetrahydrofuran, 1,4-dioxane, etc., ahalogenated aliphatic hydrocarbon solvent such as methylene chloride,etc., and toluene singly or in combination of admixture thereof. Thedehydrating agent may be used an azodicarboxylic acid derivative such astetramethylazodicarboxamide, diethylazodicarboxylate, etc., atrialkylphosphine such as tri-n-butylphosphine, etc.; and atriarylphosphine such as triphenylphosphine, etc. The reaction can becarried out at 0 to 80° C. The reaction can be also carried out by usinga corresponding p-toluenesulfonate (Xb) led from Compound (Xa), andreacting it with Compound (IX) under the similar reaction conditions asin Step 2A.

Step 6A

The reaction of removing the protective group (PROT₁) from Compound (XI)formed in Step 5A can be carried out, for example, by the deprotectingmethod of the protective group which is generally used in the organicsynthetic chemistry as described in “Protective Groups in OrganicSynthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, andoptimum method can be optionally selected depending on the kind of theprotective group. For example, when PROT₁ is2-(trimethylsilyl)ethoxymethyl group, it can be carried out by treatingwith an acid such as hydrochloric acid, trifluoroacetic acid,methanesulfonic acid, etc., in water, a water-miscible ether solventsuch as 1,4-dioxane, tetrahydrofuran, etc., or an alcohol solvent suchas methanol, ethanol, etc., or in the absence of a solvent. The reactioncan be practiced suitably at room temperature. Also, when PROT₁ isbenzyl group, it can be carried out by treating with a palladiumcatalyst such as palladium hydroxide-carbon, etc., under hydrogenatmosphere in a water-miscible ether solvent such as tetrahydrofuran,etc., or an alcohol solvent such as methanol, ethanol, etc.

Step 7A

The reaction of removing the protective group (PROT₃) from Compound(XII) formed in Step 6A can be carried out, for example, by thedeprotecting method of the protective group for the carboxyl group whichis generally used in the organic synthetic chemistry as described in“Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts,John Wiley and Sons 1991, and optimum method can be optionally selecteddepending on the kind of the protective group. For example, when PROT₃is an alkyl group such as methyl group, ethyl group, etc., it can becarried out according to the conventional manner in the esterhydrolysis, and, for example, it can be carried out by treating with analkali metal hydroxide such as potassium hydroxide, sodium hydroxide,etc., in water, an alcohol solvent such as methanol, ethanol, etc., oran ether solvent such as tetrahydrofuran, 1,4-dioxane, etc. Also, whenPROT₃ is benzyl group, removal of the protective group can be carriedout in the presence of a palladium catalyst such as palladium hydroxide,palladium carbon, etc., under hydrogen atmosphere in an alcohol solventsuch as methanol, ethanol, etc., or an ether solvent such astetrahydrofuran, 1,4-dioxane, etc. Also, when PROT₃ is tert-butyl group,it can be carried out by treating with an acid such as hydrochloricacid, trifluoroacetic acid, methanesulfonic acid, etc., in water, awater-miscible ether solvent such as 1,4-dioxane, tetrahydrofuran, etc.,or an alcohol solvent such as methanol, ethanol, etc. or in the absenceof a solvent. The reaction can be carried out suitably at roomtemperature.

(Method B) Step 1B

Compound (XIII) may be used that in which HAL₄ is chlorine atom, bromineatom or iodine atom, and preferred is that in which it is bromine atom.The dehydration reaction of Compound (X) or a salt thereof and Compound(XIII) or a salt thereof can be carried out in the same manner as in thedehydration reaction of the above-mentioned Step 5A.

Step 2B

The reaction of Compound (XIV) or a salt thereof formed in Step 1B andbis(pinacolato)diboron can be carried out in the presence of a palladiumcatalyst and a base in a suitable solvent. The solvent may be used anamide solvent such as N,N-dimethylformamide, etc., an ether solvent suchas dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, dimethoxyethane,etc., and toluene, etc., singly or in admixture thereof. The palladiumcatalyst may be used palladium chloride, palladium acetate,tetrakis(triphenylphosphine) palladium, etc., and if necessary, a ligandsuch as 1,1′-bis(diphenylphosphino)ferrocene, etc., may be used. Thebase may be used an alkali metal base such as sodium carbonate,potassium carbonate, potassium acetate, potassium phosphate, sodiumhydroxide, etc., and cesium carbonate, etc. The reaction can be carriedout at room temperature to 150° C., preferably at 80 to 120° C.

Step 3B

Compound (XVI) may be used that in which HAL₅ is chlorine atom, bromineatom or iodine atom. The coupling reaction of Compound (XV) or a saltthereof formed in Step 2B and Compound (XVI) or a salt thereof can becarried out in the same manner as in the coupling reaction of theabove-mentioned Step 3A.

Step 4B

The reaction of Compound (XVII) or a salt thereof formed in Step 3B andhydroxylamine can be carried out, for example, according to theconventional manner of the reaction of the cyano group and hydroxylaminedescribed in U.S. Pat. No. 5,576,447, etc., in a suitable solvent. Thesolvent may be used water, an alcohol solvent such as methanol, ethanol,etc., and an ether solvent such as tetrahydrofuran, 1,4-dioxane, etc.,singly or in admixture thereof. The reaction can be carried out at roomtemperature to 100° C., preferably at 50 to 80° C.

The product is treated with acetic acid-acetic anhydride according tothe conventional method, then, and stirred in a solvent such as analcohol solvent including methanol, ethanol, etc., or an ether solventsuch as tetrahydrofuran, etc., in the presence of a palladium catalystsuch as palladium carbon, etc., under hydrogen atmosphere to obtainCompound (XVIII). The reaction can be carried out under ice-cooling to50° C., preferably at room temperature.

Step 5B

Conversion from Compound (XIXa) to Compound (XX) can be carried out byreacting oxalyl chloride to Compound (XIXa) or a salt thereof in asuitable solvent, the solvent is distilled off from the reactionmixture, (trimethylsilyl)diazomethane is reacted with a product in asuitable solvent, and hydrobromic acid is acted on the product.

The solvent to be used in the reaction of Compound (XIXa) and oxalylchloride may be mentioned methylene chloride and tetrahydrofuran, etc.,and the reaction can be carried out by adding a catalytic amount ofN,N-dimethylformamide at −20 to 40° C., preferably under ice-cooling toroom temperature.

As the solvent to be used in the subsequent reaction withtrimethylsilyldiazomethane, there may be mentioned acetonitrile,tetrahydrofuran, methylene chloride, etc. The reaction can be carriedout at −20 to 40° C., preferably under ice-cooling to room temperature.

The hydrobromic acid treatment can be carried out by gradually addinghydrobromic acid to the product of the previous reaction. The reactioncan be carried out at −20 to 40° C., preferably under ice-cooling toroom temperature.

Also, conversion from Compound (XIXb) to Compound (XX) can be carriedout by reacting Compound (XIXb) or a salt thereof with a brominatingreagent such as dioxane dibromide, etc., in a suitable solvent such asmethanol, etc.

Step 6B

The reaction of Compound (XVIII) formed in Step 4B and Compound (XX) ora salt thereof formed in Step 5B can be carried out, for example,according to the method described in I. M. Mallick et al., Journal ofthe American Chemical Society, 106(23), 7252-7254, 1984, etc., in thepresence of a base in a suitable solvent. The solvent may be used water,an alcohol solvent such as methanol, ethanol, etc., an aprotic polarsolvent such as N,N-dimethylformamide, N-methylpyrrolidone, etc., ahalogenated hydrocarbon solvent such as methylene chloride, etc., andtetrahydrofuran, acetonitrile, etc., singly or in admixture thereof, andthe base may be used an alkali metal base such as potassium hydrogencarbonate, potassium carbonate, sodium ethylate, etc. The reaction canbe carried out at room temperature to 100° C., preferably at 50 to 80°C.

Subsequent Step 7B is the same as the reaction (Step 7A) correspondingto the above-mentioned Method A, and can be carried out in the samemanner as mentioned above.

Step 8B

The coupling reaction of Compound (XIV) or a salt thereof formed in Step1B and Compound (XXVI) or a salt thereof can be carried out in the samemanner as in the coupling reaction of the above-mentioned Step 3A.

(Method C)

Step 1C, Step 2C, Step 3C and Step 4C are each the same with Step 1A,Step 2A, Step 1B and Step 2B, respectively, and can be carried out inthe same manner as mentioned above.

Step 5C

The reaction of Compound (VI) or a salt thereof formed in Step 2C andCompound (XV) or a salt thereof formed in Step 4C can be carried out inthe same manner as in the coupling reaction of the above-mentioned Step3A.

Step 6C

The reaction of removing the protective group (PROT₃) from Compound (XI)formed in Step 5C can be carried out in the same manner as in theremoval reaction of the protective group of the above-mentioned Step 7A.

Step 7C

The reaction of removing the protective group (PROT₁) from Compound(XXI) formed in Step 6C can be carried out in the same manner as in theremoval reaction of the protective group of the above-mentioned Step 6A.

Step 8C

The reaction of forming Compound (XXVII) from Compound (VI) formed inStep 2C is the same as Step 2B, and can be carried out in the samemanner as in the same.

Step 9C

The reaction of Compound (XIV) or a salt thereof formed in Step 3C andCompound (XXVII) or a salt thereof formed in Step 8C can be carried outin the same manner as in the coupling reaction of the above-mentionedStep 3A.

(Method D) Step 1D

Compound (XXII) may be mentioned that in which HAL₆ is chlorine atom,bromine atom or iodine atom, PROT₄ is, for example, by the deprotectingmethod of the protective group for the carboxyl group which is generallyused in the organic synthetic chemistry as described in “ProtectiveGroups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley andSons 1991, and such a protective group may be mentioned an esterresidue, for example, an alkyl group such as methyl group, ethyl group,etc., benzyl group, etc.

Reduction of Compound (XXII) can be carried out according to theconventional manner of reducing a carboxylic acid ester to an alcohol,by treating with a reducing agent in a suitable solvent. The solvent maybe used an ether solvent such as tetrahydrofuran, ether, etc., and thereducing agent may be used isobutyl aluminum hydride, lithium aluminumhydride, lithium borohydride, etc. The reaction can be carried out at−30° C. to room temperature.

Step 2D, Step 3D

The reactions of Step 2D and Step 3D are the same as the above-mentionedStep 3C and the above-mentioned Step 4C, and can be carried out in thesame manner as mentioned above.

Step 4D

The reaction of Step 4D can be carried out in the same manner as thereaction of the above-mentioned Step 3B.

Step 5D

Oxidation of Compound (XXIV) or a salt thereof formed in Step 4D can becarried out according to the conventional manner of oxidation of analcohol, and for example, can be carried out by Swern oxidation. It canbe carried out by using an oxidizing agent such as dimethylsulfoxide ina suitable solvent. The solvent may be used a halogenated hydrocarbonsolvent such as methylene chloride, etc., and an activating agent may bepreferably used oxalyl chloride, etc. The reaction can be carried out at−78° C. to room temperature.

Step 6D

Compound (XXV) formed in Step 5D is subjected to the same reaction as inthe above-mentioned Step 1A to prepare Compound (XII).

Step 7D

The reaction of Compound (XII) formed in Step 6D and Compound (V) can becarried out in the same manner as in the above-mentioned Step 2A.

Step 8D

The reaction of removing the protective group (PROT₃) from Compound (XI)formed in Step 7D can be carried out in the same manner as in theremoval reaction of the protective group of the above-mentioned Step 7A.

Step 9D

The reaction of removing the protective group (PROT₁) from Compound(XXI) formed in Step 8D can be carried out in the same manner as in theremoval reaction of the protective group of the above-mentioned Step 7C.

In the above-mentioned (Method A), (Method B), (Method C) and (MethodD), isolation and/or purification of the product is/are carried out,these can be carried out by the usual separation and/or purificationmethods such as extraction, fractional crystallization, various kinds ofchromatographies, etc.

The thus obtained Compound (I) can be converted into a pharmaceuticallyacceptable salt depending on necessity by treating with an acid or abase corresponding to the pharmaceutically acceptable salt in a suitablesolvent. Also, the compound or a pharmaceutically acceptable saltthereof of the present invention include both of their solvent andhydrate, etc. For example, an alkali metal salt of Compound (I) can beobtained by treating Compound (I) with an alkali metal hydroxide such assodium hydroxide, potassium hydroxide, etc., or an alkali metalcarbonate such as sodium carbonate, potassium carbonate, etc., in water,a water-soluble ether solvent such as tetrahydrofuran, 1,4-dioxane,etc., a nitrile solvent such as acetonitrile, etc., an alcohol solventsuch as methanol, ethanol, etc., or a mixed solvent thereof, to preparea corresponding metal salt. Moreover, a hydrate or a solvate thereof canbe obtained by treating the same with water, a water-containing solventor a hydrated solvent or other solvents according to the conventionalmanner.

When Compound (I) or a pharmaceutically acceptable salt thereof of thepresent invention is a racemic mixture or contains optical isomers, eachoptical isomer can be separated according to the usual opticallyresolving means. For example, it can be optically resolved to a desiredoptical isomer by a fractional crystallization method due to a salt withan optically active acid or base, or by passing through a column filledwith an optically active carrier. Or else, an optically active isomer ofthe compound of the formula (I) or a pharmaceutically acceptable saltthereof may be synthesized by using an optically pure starting materialor a compound configuration of which has already been known.

The thus obtained continuous arycyclic compound (I) or apharmaceutically acceptable salt thereof of the present invention can beformulated as a medical composition containing a pharmaceuticallyeffective amount of the compound and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier may be mentioned abinder (for example, hydroxypropylcellulose, polyvinyl alcohol,polyvinylpyrrolidone, polyethylene glycol), an excipient (for example,lactose, sucrose, mannitol, sorbitol, corn starch, potato starch,crystalline cellulose, calcium carbonate), a lubricant (for example,magnesium stearate, calcium stearate, talc), a disintegrator (forexample, low-substitution degree hydroxypropylcellulose, cross-linkedcarboxymethylcellulose) and a wetting agent (for example, sodiumlaurylsulfate), etc.

The continuous arycyclic compound (I) or a pharmaceutically acceptablesalt thereof of the present invention can be administered orally orparenterally, and can be used as a suitable medical preparation. As asuitable medical preparation for oral administration, there may bementioned, for example, a solid preparation such as a tablet, granule,capsule, powder, etc., or a solution preparation, suspension preparationor emulsion preparation, etc. As a suitable medical preparation forparenteral administration, there may be mentioned a suppository, aninjection using distilled water for injection, physiological saline oraqueous glucose solution, etc., or infusion preparation, or inhalations,etc.

An administration dose of the continuous arycyclic compound (I) or apharmaceutically acceptable salt thereof of the present invention mayvary depending on an administration method, an age, body weight andconditions of a patient, and in the case of oral administration, it isgenerally administered 0.001 to 100 mg/kg/day, preferably 0.1 to 30mg/kg/day, more preferably 0.1 to 10 mg/kg/day, once a day or dividinginto 2 to 4 times. In the case of parenteral administration, it ispreferably administered 0.0001 to 10 mg/kg/day, and once a day ordividing into several times. Also, when it is transmucosallyadministered, it is preferably administered 0.001 to 100 mg/kg/day, oncea day or dividing into several times.

In the following, the present invention will be explained in detail byreferring to Examples and Experimental examples, but the presentinvention is not limited by these. Also, in the chemical formulae inExamples, a hydrogen atom on a saturated ring, a hydrogen atom on analkyl chain, and a hydrogen atom on a nitrogen atom are sometimesomitted.

EXAMPLES Example 1

1) After 40% diethyl azodicarboxylate-toluene solution (313.1 μL) wasadded dropwise to a tetrahydrofuran (3 mL) solution containing4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol(150 mg), methyl hydroxylpivalate (65.9 μL) and triphenylphosphine(180.7 mg) under ice-cooling, the mixture was stirred at roomtemperature for one hour, and at 70° C. overnight. To the mixture werefurther added methyl hydroxypivalate (22 μL), triphenylphosphine (63 mg)and 40% diethyl azodicarboxylate-toluene solution (109 μL), and themixture was stirred at 70° C. for one hour. After cooling a temperatureof the reaction mixture to room temperature, the mixture wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=88:12 to 76:24) to obtain methyl2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(144.2 mg).

MS (m/z): 550 [M+H]⁺

2) In trifluoroacetic acid (2.9 mL) and water (0.3 mL) was dissolvedmethyl2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(144 mg) under ice-cooling, and the mixture was stirred at roomtemperature overnight. To the residue obtained by concentrating thereaction mixture under reduced pressure were added chloroform and asaturated aqueous sodium bicarbonate solution. The formed insolublematerial was dissolved in methanol and combined with the organic layer.The organic layer was washed with water, and concentrated under reducedpressure. The obtained residue was pulverized by cooled ether, collectedby filtration and dried to obtain methyl2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(85.9 mg).

MS (m/z): 420 [M+H]⁺

3) In tetrahydrofuran (0.85 mL) and methanol (0.85 mL) was dissolvedmethyl2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(85 mg), 2N aqueous sodium hydroxide solution (1013.35 μL) was added tothe solution, and the mixture was stirred at room temperature overnight.Acetic acid was added to the reaction mixture, and the mixture wasconcentrated under reduced pressure. To the residue were added aceticacid, water, and a phosphate buffer (pH 6.8), and after stirring themixture, the organic layer was separated and concentrated under reducedpressure. After purification of the residue by LC-MS, it was dissolvedin water and ethyl acetate, and the liquids were separated by adding 0.1N phosphate buffer (pH 7.0). The organic layer was separated andconcentrated under reduced pressure, and the obtained residue waspulverized by cooled ethyl acetate and collected by filtration to obtain2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyridin-2-yl}phenoxy)propanoicacid (29.3 mg).

MS (m/z): 406 [M+H]⁺

4) In tetrahydrofuran (2.5 mL) was dissolved2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoicacid (250 mg), 10M aqueous sodium hydroxide solution (65 μL) was addedto the solution dividing into several times, and the mixture was stirredat room temperature overnight. The precipitate was collected byfiltration, washed with tetrahydrofuran (1 mL), and dried at 40° C.under reduced pressure to obtain sodium2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(216 mg).

MS (m/z): 404 [M−Na]⁻

Example 2

1) In methylene chloride (5 mL) was dissolved3,3,3-trifluoro-2,2-dimethylpropanoic acid (250 mg), and oxalyl chloride(279 μL) was added dropwise to the mixture. After addingN,N-dimethylformamide (one drop), the mixture was stirred at roomtemperature for one hour. After concentrating the reaction mixture underreduced pressure, acetonitrile (2 mL) was added to the residue. 2M(trimethylsilyl)diazomethane-n-hexane solution (1682 μL) was addeddropwise to the mixture under ice-cooling, and the resulting mixture wasstirred at room temperature for one hour. The reaction mixture wasice-cooled, 48% hydrobromic acid (272 μL) was added dropwise, and themixture was stirred for 15 minutes. To the reaction mixture were addedether and water, and the liquids were separated. The organic layer wasseparated, washed with a saturated aqueous sodium bicarbonate solution,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The obtained oily substance was dissolved in methylenechloride (5 mL), methyl3-(4-{5-[amino(imino)methyl]pyridin-2-yl}-phenoxy)-2,2-dimethylpropanoateacetate (558 mg), potassium carbonate (885 mg) and saturated brine (5mL) were added to the solution, and the mixture was stirred at 45° C.overnight. To the reaction mixture were added ethyl acetate and water,and the liquids were separated. The organic layer was separated, washedwith water, dried over anhydrous sodium sulfate, and the residueobtained by concentrating the reaction mixture under reduced pressurewas purified by silica gel column chromatography(chloroform:methanol=100:0 to 95:5) to obtain methyl2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(178 mg).

MS (m/z): 462 [M+H]⁺

2) In methanol (2 mL) and tetrahydrofuran (2 mL) was dissolved methyl2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}-phenoxy)propanoate(176 mg), 2N aqueous sodium hydroxide solution (900 μL) was added to thesolution, and the mixture was stirred at room temperature overnight.

Acetic acid (3 mL) was added to the mixture, and the resulting mixturewas concentrated under reduced pressure. Water was added to the residueand the formed solid was collected by filtration and dried to obtain2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoicacid (167 mg).

MS (m/z): 448 [M+H]⁺

3) In acetonitrile (4 mL) was suspended2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoicacid (175 mg), and 2N aqueous sodium hydroxide solution (391 μL) wasadded dropwise to the suspension. After adding acetonitrile (1 mL), thereaction mixture was stirred at room temperature overnight. Methanol wasadded until the reaction mixture became uniform solution, and tar-stateinsoluble material was separated by filtration. The filtrate wasconcentrated under reduced pressure, and the obtained solid residue waspulverized by ether, collected by filtration, washed with ether, anddried at room temperature in vacuum to obtain sodium2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(174 mg).

MS (m/z): 446 [M−Na]⁻

Example 3

1) By using2-(4-bromophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazole(400 mg) and methyl2,2-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)pyridin-2-yl]oxy}propanoate(537 mg), the procedure was carried out in the same manner as inReference example 1-3) to obtain methyl2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]propanoate(490 mg).

MS (m/z): 550 [M+H]⁺

2) In ethanol (10 mL) was dissolved methyl2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]-propanoate(490 mg), 2N aqueous sodium hydroxide solution (2.2 mL) was added to thesolution, and the mixture was stirred at room temperature overnight. Thereaction mixture was ice-cooled and neutralized with 2N hydrochloricacid (2.2 mL), then, ethyl acetate and saturated brine were added to themixture, and the liquids were separated. The organic layer wasseparated, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 97:3) to obtain2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-pyridin-2-yl)oxy]propanoicacid (287 mg).

MS (m/z): 536 [M+H]⁺

3) In trifluoroacetic acid (10 mL) and water (1 mL) was dissolved2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-phenyl}pyridin-2-yl)oxy]propanoicacid (287 mg), and the mixture was stirred at room temperatureovernight. The residue obtained by concentrating the reaction mixtureunder reduced pressure was dissolved in acetic acid, and the mixture wasconcentrated under reduced pressure. The obtained solid residue waspulverized by adding ether, collected by filtration, washed with etherand dried to obtain2,2-dimethyl-3-[(5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]propanoicacid (175 mg).

MS (m/z): 406 [M+H]⁺

Example 4

1) By using methyl3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)-phenoxy]-2,2-dimethylpropanoate(375 mg) and2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(300 mg), the procedure was carried out in the same manner as inReference example 1-3) to obtain methyl3-(2-fluoro-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate.

MS (m/z): 568 [M+H]⁺

2) In methanol (6 mL) and tetrahydrofuran (3 mL) was dissolved methyl3-(2-fluoro-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoateobtained in the above-mentioned 1), ION aqueous sodium hydroxidesolution (0.3 mL) was added to the solution, and the mixture was stirredat room temperature overnight, and then refluxed for 4 hours. Theresidue obtained by concentrating the reaction mixture under reducedpressure was dissolved in trifluoroacetic acid (10 mL) and water (1 mL),and the mixture was stirred at room temperature overnight. The residueobtained by concentrating the reaction mixture under reduced pressurewas dissolved in acetic acid (2 mL), and the solution was concentratedunder reduced pressure. To the obtained residue were added ethyl acetate(0.5 mL) and water (10 mL), and the mixture was stirred room temperaturefor 2 hours. Powdery solid was collected by filtration, washed withwater, dried, washed with ether and dried to obtain3-(2-fluoro-4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoicacid (281 mg).

MS (m/z): 424 [M+H]⁺

Example 5

1) In tetrahydrofuran (5.0 mL) were mixed2-chloro-4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(400 mg), methyl2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]propanoate(409.4 mg), palladium acetate (22.9 mg), potassium phosphate (433.3 mg),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (83.8 mg), and themixture was stirred at 70° C. in nitrogen atmosphere overnight. Asaturated aqueous sodium bicarbonate solution was added to the mixtureand after stirring the mixture, ethyl acetate was added to the same andthe liquids were separated. The organic layer was separated, washed withsaturated brine, and the residue obtained by concentrating the organiclayer under reduced pressure was purified by silica gel columnchromatography (n-hexane:ethyl acetate=90:10 to 65:35) to obtain methyl2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-propanoate(152 mg).

MS (m/z): 564 [M+H]⁺

2) By using methyl2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate(150 mg), the procedure was carried out in the same manner as in Example3-2) to obtain2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoicacid (141 mg).

MS (m/z): 550 [M+H]⁺

3) By using2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoicacid (140 mg), the procedure was carried out in the same manner as inExample 3-3) to obtain2,2-dimethyl-3-(4-{4-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}-phenoxy)propanoicacid (35.9 mg).

MS (m/z): 420 [M+H]⁺

Example 6

1) By using 1-(trifluoromethyl)-1-cyclopropanecarboxylic acid (300 mg),and methyl3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoateacetate (453 mg), the procedure was carried out in the same manner as inExample 2-1) to obtain methyl2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate(439 mg).

MS (m/z): 460 [M+H]⁺

2) By using methyl2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate(369 mg), the procedure was carried out in the same manner as in Example2-2) to obtain2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoicacid (320 mg).

MS (m/z):446[M+H]⁺

3) By using2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoicacid (320 mg), the procedure was carried out in the same manner as inExample 2-3) to obtain sodium2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate(313 mg).

MS (m/z):444 [M−Na]⁻

Example 7

1) In tetrahydrofuran (75 mL) was dissolved methyl5-chloropyrazin-2-carboxylate (2.589 g), 1M diisobutyl aluminumhydride-tetrahydrofuran solution (30 mL) was added dropwise to thesolution at 0° C., and the mixture was stirred at the same temperaturefor 15 minutes. To the mixture were added water and 1N hydrochloricacid, then, a saturated aqueous sodium bicarbonate solution was added tothe same to make the pH to 7. The mixture was filtered through Celite,and then, extracted with chloroform 3 times. The organic layer wasseparated, dried over anhydrous sodium sulfate, and the residue obtainedby concentrating the same under reduced pressure was purified by silicagel column chromatography (n-hexane:ethyl acetate=90:10 to 65:35 to50:50) to obtain (5-chloropyrazin-2-yl)methanol (465 mg).

MS (m/z): 147/145 [M+H]⁺

2) In N,N-dimethylacetamide (6.4 mL) and 2M aqueous sodium carbonatesolution (6.4 mL) were suspended (5-chloropyrazin-2-yl)methanol (460 mg)and methyl2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]propanoate(1.600 g), palladium chloride (dppf) methylene chloride complex (261 mg)was added to the suspension, and the mixture was stirred at 80° C.overnight. To the reaction mixture were added ethyl acetate and water,and the mixture was filtered through Celite. The organic layer wasseparated, and the aqueous layer was extracted twice with ethyl acetate.The organic layers were combined, washed twice with water, washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=70:30 to 40:60 to 0:100)to obtain methyl3-{4-[5-(hydroxyl-methyl)pyrazin-2-yl]phenoxy}-2,2-dimethylpropanoate(660 mg).

MS (m/z): 317 [M+H]⁺

3) To a methylene chloride (11 mL) solution of oxalyl chloride (355 μL)was added dropwise a methylene chloride (2 mL) solution ofdimethylsulfoxide (450 μL) at −78° C., and the mixture was stirred for15 minutes. To the mixture was added dropwise a methylene chloride (6mL) solution of methyl3-{4-[5-(hydroxymethyl)pyrazin-2-yl]-phenoxy}-2,2-dimethylpropanoate(655 mg) at −78° C., and the mixture was stirred for 10 minutes, and themixture was stirred for 1 hour and 30 minutes. Triethylamine (2.05 mL)was added to the mixture, the temperature of the mixture was raised to0° C., and the mixture was stirred for 30 minutes. To the reactionmixture were added a saturated aqueous ammonium chloride solution andethyl acetate, and the organic layer was separated. The aqueous layerwas extracted twice with ethyl acetate. The organic layers werecombined, washed twice with water, and with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=95:5 to 75:25) to obtain methyl3-{4-[5-formylpyrazin-2-yl]phenoxy}-2,2-dimethylpropanoate (585 mg).

MS (m/z): 315 [M+H]⁺

4) By using methyl3-{4-[5-formylpyrazin-2-yl]phenoxy}-2,2-dimethylpropanoate (580 mg), theprocedure was carried out in the same manner as in Reference example1-1) to obtain methyl2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoate(640 mg).

MS (m/z): 421 [M+H]⁺

5) By using methyl2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyrazin-2-yl}phenoxy)propanoate(640 mg), the procedure was carried out in the same manner as inReference example 1-2) to obtain methyl2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoate(759 mg).

MS (m/z): 551 [M+H]⁺

6) By using methyl2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoate(755 mg), the procedure was carried out in the same manner as in Example3-2) to obtain2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoicacid (545 mg).

MS (m/z): 537 [M+H]⁺

7) By using2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoicacid (540 mg), the procedure was carried out in the same manner as inExample 3-3) to obtain2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoicacid (335 mg).

MS (m/z): 407 [M+H]⁺

Example 8

1) By using2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]-2-pyridyl]phenol(224 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (284 mg), theprocedure was carried out in the same manner as in Example 1-1) toobtain tert-butyl2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]propanoate(104 mg).

MS (m/z): 606 [M+H]⁺

2) In trifluoroacetic acid (5 mL) and water (0.5 mL) was dissolvedtert-butyl2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]-2-pyridyl]phenoxy]propanoate(103 mg), and the mixture was stirred at room temperature overnight. Theresidue obtained by concentrating the reaction mixture under reducedpressure was dissolved in tetrahydrofuran, and 1N aqueous sodiumhydroxide solution was added to the mixture to adjust a pH thereof to 7.To the mixture were added 0.1N phosphate buffer, ethyl acetate andwater, and the liquids were separated. The organic layer was separated,dried over anhydrous sodium sulfate, and ether was added to the residueobtained by concentrating the solution under reduced pressure topulverize the precipitates to obtain2,2-dimethyl-3-[2-methyl-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoicacid (59.1 mg).

MS (m/z): 420 [M+H]⁺

By using the corresponding starting materials, the following mentionedcompounds were synthesized in the same manner as in Example 8.

TABLE 1 Example Starting substance Product MS (m/z)  9

420 [M + H]⁺ 10

421 [M + H]⁺ 11

392 [M + H]⁺ 12

402 [M + H]⁺

Example 13

1) By using5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridin]pyridin-2-ol(200 mg), the procedure was carried out in the same manner as in Example1-1) to obtain methyl2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoate(156 mg).

MS (m/z): 551 [M+H]⁺

2) By using methyl2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoate(148 mg), the procedure was carried out in the same manner as in Example3-2) to obtain2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoicacid (135 mg).

MS (m/z): 537 [M+H]⁺

3) By using2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoicacid (135 mg), the procedure was carried out in the same manner as inExample 3-3) to obtain2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoicacid.

MS (m/z): 407 [M+H]⁺

By using the corresponding starting materials, the following mentionedcompounds were synthesized in the same manner as in Example 13.

TABLE 2 Example Starting substance Product MS (m/z) 14

418 [M + H]⁺ 15

406 [M + H]⁺ 16

433 [M + H]⁺ 17

433 [M + H]⁺

Example 18

1) By using4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol(400 mg) and benzyl 4-hydroxy-2,2-dimethylbutanoate (306 mg), theprocedures were carried out in the same manner as in Example 1-1) and1-2) to obtain benzyl2,2-dimethyl-4-[4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridin]phenoxy]butanoate(366 mg).

MS (m/z): 510 [M+H]⁺

2) In tetrahydrofuran (20 mL) was dissolved benzyl2,2-dimethyl-4-[4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridin]phenoxy]butanoate(365 mg), 10% palladium-carbon (400 mg) was added to the solution, andthe mixture was stirred under hydrogen atmosphere at room temperaturefor 6 hours. The palladium-carbon was filtered off, and washed withtetrahydrofuran and chloroform. The filtrate was concentrated underreduced pressure, isopropanol and isopropyl ether were added to theobtained solid residue to suspend therein, and the solid was collectedby filtration to obtain2,2-dimethyl-4-[4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridin]phenoxy]butanoicacid (200 mg).

MS (m/z): 420 [M+H]⁺

Example 19

1) In N,N-dimethylformamide (1.4 mL) was dissolved4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol(305 mg), 60% sodium hydride (34 mg) was added to the solution at roomtemperature and the mixture was stirred for one hour. To the reactionmixture was added an N,N-dimethylformamide (1 mL) solution containingmethyl 2-ethyl-2-(p-tolylsulfonyloxymethyl)butanoate (264 mg) underice-cooling. The reaction mixture was stirred at 100° C. overnight. Tothe reaction mixture was added 60% sodium hydride (9 mg) underice-cooling, and the mixture was stirred at 100° C. overnight. To thereaction mixture were added a saturated aqueous ammonium chloridesolution and ethyl acetate, and the liquids were separated. The aqueouslayer was separated, and extracted with ethyl acetate. The organiclayers were combined, washed with water and saturated brine in thisorder, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=95:5 to 50:50) to obtain methyl2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]butanoate(248 mg).

MS (m/z): 578 [M+H]⁺

2) By using methyl2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]butanoate(474 mg), the procedure was carried out in the same manner as in Example3-2) to obtain2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]-methyl]butanoicacid (414 mg).

MS (m/z):564 [M+H]⁺

3) By using2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]butanoicacid (465 mg), the procedure was carried out in the same manner as inExample 3-3) to obtain2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]methyl]butanoicacid (249 mg).

MS (m/z): 434 [M+H]⁺

By using the corresponding starting materials, the following mentionedcompounds were synthesized in the same manner as in Example 19.

TABLE 3 Example Starting substance Product MS (m/z) 20

432 [M + H]⁺ 21

448 [M + H]⁺ 22

435 [M + H]⁺ 23

435 [M + H]⁺

By using the corresponding carboxylic acid, the following compounds weresynthesized in the same manner as in Example 2.

TABLE 4 Example Starting substance Product MS (m/z) 24

434 [M + H]⁺ 25

408 [M + H]⁺ 26

394 [M + H]⁺ 27

392 [M + H]⁺ 28

380 [M + H]⁺ 29

408 [M + H]⁺ 30

406 [M + H]⁺ 31

434 [M + H]⁺ 32

380 [M + H]⁺ 33

428 [M + H]⁺ 34

456 [M + H]⁺

Example 35

1) To methylene chloride (10 mL) was added3,3,3-trifluoro-2,2-dimethylpropanoic acid (1000 mg), and oxalylchloride (1132 μL) was added dropwise to the mixture.N,N-dimethylformamide (5 drops) was added to the mixture, and theresulting mixture was stirred at room temperature for one hour. Afterconcentrating the reaction mixture under reduced pressure, acetonitrile(7 mL) was added to the residue. 2M trimethylsilyldiazomethane-n-hexanesolution (6814 μL) was added dropwise to the mixture at 0° C., and themixture was stirred at room temperature for 1.5 hours. After cooling themixture to 0° C., 48% hydrobromic acid (1.1 mL) was added dropwise tothe mixture, and the mixture was stirred for 30 minutes. To the reactionmixture were added ethyl acetate and saturated aqueous sodiumbicarbonate solution, and the liquids were separated. The organic layerwas separated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain2-bromo-1-[1-(trifluoromethyl)cyclopropyl]ethanone (1413 mg).

NMR (400 MHz, CDCl₃) σ: 1.47-1.75 (m, 4H), 4.38 (s, 3H)

2) To methylene chloride (10 mL) and saturated brine (10 mL) were addedmethyl3-[4-(5-carbamimidoyl-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate(500 mg) and potassium carbonate (430.3 mg), then,2-bromo-1-[1-(trifluoromethyl)cyclopropyl]-ethanone (431.6 mg) was addedto the mixture, and the resulting mixture was stirred at 50° C.overnight. The organic layer was separated and the residue obtained byconcentrating the same under reduced pressure was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=75:25 to 25:75) to obtainmethyl2,2-dimethyl-3-[4-(4-methyl-5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]propanoate(423 mg).

MS (m/z): 474 [M+H]⁺

3) By using methyl2,2-dimethyl-3-[4-(4-methyl-5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]propanoate(422 mg), the procedure was carried out in the same manner as in Example2-2) to obtain2,2-dimethyl-3-[4-(4-methyl-5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]-propanoicacid (378 mg).

MS (m/z): 460 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Example 35.

TABLE 5 Example Starting substance 1 Starting substance 2 Product MS(m/z) 36

461 [M + H]⁺ 37

474 [M + H]⁺ 38

460 [M + H]⁺ 39

460 [M + H]⁺ 40

461 [M + H]⁺ 41

474 [M + H]⁺ 42

488 [M + H]⁺ 43

474 [M + H]⁺ 44

476 [M + H]⁺ 45

464 [M + H]⁺ 46

475 [M + H]⁺ 47

463 [M + H]⁺ 48

461 [M + H]⁺ 49

447 [M + H]⁺ 50

449 [M + H]⁺ 51

465 [M + H]⁺ 52

492 [M + H]⁺ 53

466 [M + H]⁺

Example 54

1) N,N-dimethylformamide (30 mL) was added to4-bromo-2-fluorobenzonitrile (2000 mg), methyl2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate(4191 mg) and palladium chloride (dppf) methylene chloride complex (408mg), and after adding 2N aqueous sodium carbonate solution (15 mL) tothe mixture, the atmosphere was replaced with nitrogen and the resultingmixture was stirred at 60° C. for 7 hours. Ethyl acetate and water wereadded to the reaction mixture, and the liquids were separated. Theorganic layer was separated, washed with a saturated brine, and theresidue obtained by concentrating the mixture under reduced pressure waspurified by silica gel column chromatography (n-hexane:ethylacetate=90:10 to 80:20) to obtain methyl3-{[5-(4-cyano-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate(3587 mg).

MS (m/z): 343 [M+H]⁺

2) A mixture in which methanol (20 mL) and tetrahydrofuran (20 mL) wereadded to methyl3-{[5-(4-cyano-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate(3.55 g) and hydroxylamine (50% aqueous solution, 13.7 g) was stirred at80° C. for 5 hours. After concentrating the mixture under reducedpressure, chloroform and water were added to the residue, and theliquids were separated. The organic layer was separated, washed with asaturated brine, concentrated under reduced pressure and dried to obtainmethyl3-({5-[3-fluoro-4-(N-hydroxycarbamimidoyl)phenyl]-4-methylpyridin-2-yl}oxy)-2,2-dimethylpropanoate(3.66 g).

MS (m/z): 376 [M+H]⁺

3) Acetic anhydride (1.62 mL) was added to an acetic acid (10 mL)solution containing methyl3-({5-[3-fluoro-4-(N-hydroxycarbamimidoyl)phenyl]-4-methylpyridin-2-yl}-oxy)-2,2-dimethylpropanoate(3.65 g), and the mixture was stirred at room temperature for 5 hours.The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in methanol (30 mL), 10% palladium carbon (50%,365 mg) was added to the resulting solution, and the mixture was stirredunder hydrogen atmosphere at room temperature for 13 hours. The catalystwas filtered off by using a membrane filter, and the filtrate wasconcentrated under reduced pressure. Ether was added to the obtainedresidue, and the precipitated solid was collected by filtration, washedwith ether and dried to obtain methyl3-{[5-(4-carbamimidoyl-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoateacetic acid salt (2.45 g).

MS (m/z): 360 [M+H]⁺

4) A mixture in which methylene chloride (8 mL) and a saturated brine (8mL) were added to methyl3-{[5-(4-carbamimidoyl-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoateacetic acid salt (400 mg),2-bromo-1-[1-(trifluoromethyl)cyclopropyl]ethanone (289 mg) andpotassium carbonate (404 mg) was stirred at 50° C. for 8 hours. Theorganic layer was separated, and concentrated under reduced pressure.The obtained residue was dissolved in tetrahydrofuran (2.0 mL) andmethanol (2.0 mL), and after adding 2N aqueous sodium hydroxide solution(3.0 mL) to the solution, the resulting mixture was stirred at 50° C.for 3 hours. The mixture was diluted by ethyl acetate, and then,neutralized by adding 1N hydrochloric acid. The organic layer wasseparated, ether was added to the residue obtained by concentrating themixture under reduced pressure and the resulting mixture was stirred.The precipitated solid was collected by filtration and dried to obtain3-{[5-(3-fluoro-4-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}phenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoicacid (339 mg).

MS (m/z): 478 [M+H]⁺

Example 55

1) In methanol (30 mL) was dissolved 1-cyclobutylethanone (1.05 g),dioxane dibromide (2.68 g) was added to the solution, and the mixturewas stirred at room temperature for 1 hour and 40 minutes. To thereaction mixture was added a saturated aqueous sodium bicarbonatesolution, then, water was added to the same and the mixture wasextracted with ether. The organic layer was separated, washed withsaturated brine, and dried over anhydrous sodium sulfate. The residueobtained by concentrating the mixture under reduced pressure wasdissolved in methylene chloride (20 mL), then, methyl3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoateacetate (700 mg), potassium carbonate (1.25 g) and saturated brine (20mL) were added to the solution, and the resulting mixture was stirred at50° C. overnight. The reaction mixture was separated, and the aqueouslayer was extracted with methylene chloride. The organic layers werecombined, and dried over anhydrous sodium sulfate. The residue obtainedby concentrating the reaction mixture under reduced pressure waspurified by NH-silica gel column chromatography (n-hexane:ethylacetate=65:35 to 15:85) and then by silica gel column chromatography(n-hexane:ethyl acetate=65:35 to 20:80) to obtain methyl3-[4-[5-(5-cyclobutyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate(266 mg).

MS (m/z): 406 [M+H]⁺

2) By using methyl3-[4-[5-(5-cyclobutyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate(260 mg), the procedure was carried out in the same manner as in Example2-2) to obtain3-[4-[5-(5-cyclobutyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoicacid (230 mg).

MS (m/z): 392 [M+H]⁺

By using the corresponding ketone, the following compounds weresynthesized in the same manner as in Example 55.

TABLE 6 MS Example Ketone Product (m/z) 56

420 [M + H]⁺ 57

394 [M + H]⁺

Example 58

1) By using methyl3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoateacetate (400 mg), and 1-bromobutan-2-one (234 mg), the procedure wascarried out in the same manner as in Example 35(2) to obtain methyl3-[4-[5-(5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate(397 mg).

MS (m/z): 380 [M+H]⁺

2) By using methyl3-[4-[5-(5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate(270 mg), the procedure was carried out in the same manner as in Example2-2) to obtain3-[4-[5-(5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoicacid (218 mg).

MS (m/z): 366 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Example 58.

TABLE 7 Ex- Starting am- substance MS ple Starting substance 1 2 Product(m/z) 59

395 [M + H]⁺

Example 60

1) To dimethoxyethane (12 mL) were added2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(489 mg), methyl1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]methyl]cyclopropanecarboxylate (500 mg), tetrakis(triphenylphosphine)palladium (134 mg) and2M aqueous sodium carbonate solution (2.32 mL), and the mixture wasstirred at 80° C. under nitrogen atmosphere overnight. The reactionmixture was passed through NH-silica gel short column and washed withethyl acetate. The filtrate was concentrated under reduced pressure, andthe obtained residue was purified by NH-silica gel column chromatography(n-hexane:ethyl acetate=88:12 to 71:29) to obtain methyl1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]-cyclopropanecarboxylate (491 mg).

MS (m/z): 548 [M+H]⁺

2) By using methyl1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]cyclopropanecarboxylate (484 mg), the procedure was carried out in the same manneras in Example 3-2) to obtain1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]-methyl]cyclopropanecarboxylicacid (439 mg).

MS (m/z): 534 [M+H]⁺

3) By using1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]cyclopropanecarboxylicacid (431 mg), the procedure was carried out in the same manner as inExample 3-3) to obtain1-[[4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]methyl]cyclopropanecarboxylicacid (235.7 mg).

MS (m/z): 404 [M+H]⁺

Example 61

1) A mixture in which tetrahydrofuran (6 mL) was added to5-bromo-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(542 mg), methyl2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate(372 mg), potassium phosphate (302 mg), palladium acetate (8 mg) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (29 mg) was stirredunder nitrogen atmosphere at 50° C. for 6 hours. After cooling themixture to room temperature, a saturated aqueous sodium bicarbonatesolution, water and ethyl acetate were added to the mixture and theresulting mixture was stirred. The organic layer was separated, washedwith a saturated brine, and the residue obtained by concentrating underreduced pressure was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 60:40) to obtain methyl2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoate(100 mg).

MS (m/z): 565 [M+H]⁺

2) Methanol (0.7 mL) and tetrahydrofuran (0.7 mL) were added to methyl2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoate(99 mg), and after adding 2N aqueous sodium hydroxide solution (0.7 mL)to the mixture, the resulting mixture was stirred at 50° C. for 2 hours.To the reaction mixture was added ethyl acetate, and the mixture wasneutralized by 2N hydrochloric acid. The organic layer was separated,washed with a saturated brine, and the residue obtained by concentratingthe mixture under reduced pressure was purified by silica gel columnchromatography (n-hexane:ethyl acetate=76:24 to 0:100) to obtain2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoicacid (81 mg).

MS (m/z): 551 [M+H]⁺

3) In trifluoroacetic acid (2.0 mL) and water (0.1 mL) was dissolved2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoicacid (80 mg), and the solution was stirred at room temperature for 7hours. To the solution was added 2N aqueous sodium hydroxide solution tomake a pH of the same 2 to 3, and the resulting mixture was extractedwith ethyl acetate. The extract was washed with a saturated brine, theorganic layer was separated and concentrated under reduced pressure.Isopropyl ether was added to the obtained residue, and the precipitatedsolid was collected by filtration and dried under reduced pressure toobtain2,2-dimethyl-3-({4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoicacid (30 mg).

MS (m/z): 421 [M+H]⁺

Example 62

1) N,N-dimethylformamide (4 mL) was added to2-(4-bromo-2-fluorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(500 mg), methyl2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate(477 mg) and palladium chloride (dppf) methylene chloride complex (46mg), and after adding 2N aqueous sodium carbonate solution (1.71 mL) tothe mixture, the atmosphere was replaced with nitrogen and the resultingmixture was stirred at 60° C. for 5 hours. To the reaction mixture wereadded ethyl acetate and water, and the liquids were separated. Theorganic layer was separated, washed with a saturated brine, and theresidue obtained by concentrating the mixture under reduced pressure waspurified by silica gel column chromatography (n-hexane:ethylacetate=95:5 to 82:18) to obtain methyl3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate(677 mg).

MS (m/z): 582 [M+H]⁺

2) Methanol (3.0 mL) and tetrahydrofuran (3.0 mL) were added to methyl3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate(660 mg), and after adding 2N aqueous sodium hydroxide solution (4.0 mL)to the mixture, the resulting mixture was stirred at 50° C. for 2 hours.Ethyl acetate was added to the reaction mixture, and the mixture wasneutralized by 2N hydrochloric acid. The organic layer was separated,washed with a saturated brine, and concentrated under reduced pressureto obtain3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoicacid (721 mg).

MS (m/z): 568 [M+H]⁺

3) In trifluoroacetic acid (2.0 mL) and water (0.1 mL) was dissolved3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoicacid (640 mg), and the solution was stirred at room temperature for 10hours. The solution was neutralized by adding 2N aqueous sodiumhydroxide solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with a saturated brine, the organiclayer was separated and concentrated under reduced pressure. Ether wasadded to the obtained residue, and the precipitated solid was collectedby filtration and dried under reduced pressure to obtain3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoicacid (432 mg).

MS (m/z): 438 [M+H]⁺

Example 63

1) N,N-dimethylformamide (2 mL) was added to2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(297 mg), methyl2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate(228 mg) and palladium chloride (dppf) methylene chloride complex (27mg), and after adding 2N aqueous sodium carbonate solution (0.98 mL) tothe mixture, the atmosphere was replaced with nitrogen and the resultingmixture was stirred at 60° C. for 5 hours. To the reaction mixture wereadded ethyl acetate and water, and the liquids were separated. Theorganic layer was separated, washed with a saturated brine, and theresidue obtained by concentrating the mixture under reduced pressure waspurified by silica gel column chromatography (n-hexane:ethylacetate=94:6 to 82:18) to obtain methyl3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate(278 mg).

MS (m/z): 598/600 [M+H]⁺

2) Methanol (1.5 mL) and tetrahydrofuran (1.5 mL) were added to methyl3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate(274 mg), and after adding 2N aqueous sodium hydroxide solution (1.5 mL)to the mixture, the resulting mixture was stirred 50° C. for 2 hours.Ethyl acetate was added to the reaction mixture, and the resultingmixture was neutralized by 1N hydrochloric acid. The organic layer wasseparated, washed with a saturated brine, and concentrated under reducedpressure to obtain3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoicacid (279 mg).

MS (m/z): 584/586 [M+H]⁺

3) In trifluoroacetic acid (1.0 mL) and water (0.05 mL) was dissolved3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoicacid (268 mg), and the solution was stirred at room temperature for 10hours. The solution was neutralized by adding 2N aqueous sodiumhydroxide solution, and extracted with ethyl acetate. The extract waswashed with a saturated brine, and the organic layer was separated andconcentrated under reduced pressure. Ether was added to the obtainedresidue, and the precipitated solid was collected by filtration anddried under reduced pressure to obtain3-[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoicacid (133 mg).

MS (m/z): 454/456 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Example 60.

TABLE 8 Exam- Starting Starting ple substance 1 substance 2 64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

Exam- MS ple Product (m/z) 64

424 [M + H]⁺ 65

420 [M + H]⁺ 66

407 [M + H]⁺ 67

407 [M + H]⁺ 68

406 [M + H]+ 69

456 [M + H]⁺ 70

432 [M + H]⁺ 71

418 [M + H]⁺ 72

421 [M + H]+ 73

420 [M + H]⁺ 74

420 [M + H]⁺ 75

442 [M + H]⁺ 76

424 [M + H]⁺ 77

434 [M + H]⁺ 78

420 [M + H]⁺ 79

424 [M + H]⁺ 80

442 [M + H]⁺ 81

435 [M + H]⁺ 82

458/460 [M + H]⁺ 83

425 [M + H]⁺ 84

442 [M + H]⁺

Example 85

1) By using 4-chloro-3-ethylphenol (2000 mg) and methyl hydroxypivalate(2025 mg), the procedure was carried out in the same manner as inExample 1-1) to obtain methyl3-(4-chloro-3-ethylphenoxy)-2,2-dimethylpropanoate (2951 mg).

MS (m/z): 288/290 [M+NH₄]⁺

2) By using methyl 3-(4-chloro-3-ethylphenoxy)-2,2-dimethylpropanoate(2000 mg), the procedure was carried out in the same manner as inReference example 6-2) to obtain methyl3-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]-2,2-diethylpropanoate(2311 mg).

MS (m/z): 380 [M+NH₄]⁺

3) By using methyl3-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]-2,2-diethylpropanoate(200 mg) and2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(233.2 mg), the procedure was carried out in the same manner as inReference example 1-3) to obtain methyl3-(3-ethyl-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate(94 mg).

MS (m/z): 578 [M+H]⁺

4) By using methyl3-(3-ethyl-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate(80 mg), the procedures were carried out in the same manner as inExample 4-1) and 4-2) to obtain3-(3-ethyl-4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoicacid (434 mg).

MS (m/z): 434 [M+H]⁺

Example 86

1) By using benzyl3-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,2-dimethylpropanoate(1.03 g) and2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(494 mg), the procedure was carried out in the same manner as inReference example 1-3) to obtain benzyl3-[3-methoxy-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate(639 mg).

MS (m/z): 656 [M+H]⁺

2) By using benzyl3-[3-methoxy-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate(638 mg), the procedure was carried out in the same manner as in Example1-2) to obtain benzyl3-[3-methoxy-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate.

MS (m/z): 526 [M+H]⁺

3) By using benzyl3-[3-methoxy-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoateobtained in the above-mentioned 2), the procedure was carried out in thesame manner as in Example 18-2) to obtain3-[3-methoxy-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoicacid (246 mg).

MS (m/z): 436 [M+H]⁺

Example 87

1) In tetrahydrofuran (100 mL) was dissolved methyl6-chloropyridazin-3-carboxylate (1.726 g), the solution was cooled to 0°C., 1M diisobutylaluminum hydride-tetrahydrofuran solution (20 mL) wasadded dropwise to the solution, and the mixture was stirred at the sametemperature for 20 minutes. To the reaction mixture were successivelyadded water (10 mL) and 1N hydrochloric acid (20 mL) at 0° C. Afteradding a saturated aqueous sodium bicarbonate solution to the mixture atroom temperature, the mixture was extracted with chloroform. The extractwas dried over anhydrous sodium sulfate, and the residue obtained byconcentrating the extract under reduced pressure was purified by silicagel column chromatography (n-hexane:ethyl acetate=90:10 to 25:75) toobtain (6-chloropyridazin-3-yl)methanol (177 mg).

MS (m/z): 147/145 [M+H]⁺

2) By using (6-chloropyridazin-3-yl)methanol (170 mg), and methyl3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]-2,2-dimethylpropanoate(606 mg), the procedure was carried out in the same manner as inReference example 1-3) to obtain methyl3-{4-[6-(hydroxymethyl)pyridazin-3-yl]phenoxy}-2,2′-dimethylpropanoate(188 mg).

MS (m/z): 317 [M+H]⁺

3) To a methylene chloride (8 mL) solution containing oxalyl chloride(278 μL) was added dropwise a methylene chloride solution (2 mL)containing dimethylsulfoxide (350 μL) at −78° C., and the mixture wasstirred at the same temperature for 10 minutes. A methylene chloride (5mL) containing methyl3-{4-[6-(hydroxymethyl)pyridazin-3-yl]phenoxy}-2,2′-dimethylpropanoate(519 mg) was added dropwise to the mixture over 10 minutes, and themixture was stirred at the same temperature for 1 hour. Triethylamine(1.6 mL) was added dropwise to the mixture at 0° C., and the mixture wasstirred for 30 minutes. To the reaction mixture were added a saturatedaqueous ammonium chloride solution and ethyl acetate, and the liquidswere separated. The aqueous layer was extracted twice with ethylacetate. The organic layers were combined, washed successively withwater (twice), and saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=90:10 to 50:50) to obtain methyl3-[4-(6-formylpyridazin-3-yl)phenoxy]-2,2′-dimethylpropanoate (443 mg).

MS (m/z): 315 [M+H]⁺

4) By using methyl3-[4-(6-formylpyridazin-3-yl)phenoxy]-2,2′-dimethylpropanoate (443 mg),the procedure was carried out in the same manner as in Reference example1-1) to obtain methyl2,2-dimethyl-3-(4-{6-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyridazin-3-yl}phenoxy)propanoate(360 mg).

MS (m/z): 421 [M+H]⁺

5) By using methyl2,2-dimethyl-3-(4-{6-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyridazin-3-yl}phenoxy)propanoate(359 mg), the procedure was carried out in the same manner as inReference example 1-2) to obtain methyl2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoate(309 mg).

MS (m/z): 551 [M+H]⁺

6) By using methyl2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoate(309 mg), the procedure was carried out in the same manner as in Example3-2) to obtain2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoicacid (259 mg).

MS (m/z): 537 [M+H]⁺

7) By using2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoicacid (257 mg), the procedure was carried out in the same manner as inExample 3-3) to obtain2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoicacid (194 mg).

MS (m/z): 407 [M+H]⁺

Example 88

1) By using 1-(trifluoromethyl)-1-cyclobutane carboxylic acid (300 mg),and methyl3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoateacetate (415 mg), the procedure was carried out in the same manner as inExample 2-1) to obtain methyl2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate(369 mg).

MS (m/z): 474 [M+H]⁺

2) By using methyl2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate(367 mg), the procedure was carried out in the same manner as in Example2-2) to obtain2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoicacid (350 mg).

MS (m/z): 460 [M+H]⁺

3) By using2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoicacid (350 mg), the procedure was carried out in the same manner as inExample 2-3) to obtain sodium2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate(296 mg).

MS (m/z): 458 [M−Na]⁻

Example 89

1) Dimethoxyethane (10 mL) and 2M aqueous sodium carbonate solution(1290 μL) were added to tert-butyl3-[(5-chloropyrazin-2-yl)oxy]-2,2-dimethylpropanoate (185 mg),tetrakistriphenylphosphine palladium (75 mg) and2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenyl]-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(363 mg), and the mixture was stirred at 80° C. for 4 hours. Thereaction mixture was cooled to room temperature, and filtered by usingCelite. To the filtrate were added ethyl acetate and water, and theliquids were separated. The organic layer was separated, washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=99:1 to 90:10) to obtaintert-butyl2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]propanoate(256.2 mg).

MS (m/z): 593 [M+H]⁺

2) By using tert-butyl2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]propanoate(256 mg), the procedure was carried out in the same manner as in Example8-2) to obtain2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]-propanoicacid (122.7 mg).

MS (m/z): 407 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Example 89.

TABLE 9 Exam- Starting Starting ple substance 1 substance 2 90

91

92

Exam- MS ple Product (m/z) 90

424 [M + H]⁺ 91

425 [M + H]⁺ 92

408 [M + H]⁺

Example 93

1) By using 1-benzyl-2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole(815 mg) and methyl2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]-propanoate(1.43 g), the procedure was carried out in the same manner as inReference example 1-3) to obtain methyl3-({4′-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-biphenyl-4-yl}oxy)-2,2-dimethylpropanoate(901 mg).

MS (m/z): 509 [M+H]⁺

2) By using methyl3-({4′-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoate(900 mg), the procedure was carried out in the same manner as in Example3-2) to obtain3-({4′-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoicacid (832 mg).

MS (m/z): 495 [M+H]⁺

3) The mixture of3-({4′-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoicacid (830 mg), 20% palladium hydroxide-carbon (850 mg) andtetrahydrofuran (20 mL) was stirred at 60° C. under hydrogen atmospherefor 6 hours. Nitrogen gas was passed through the reaction mixture, andthe mixture was diluted with chloroform. The mixture was filtered byusing a membrane filter, and the filtrate was washed withtetrahydrofuran, methanol and chloroform. The filtrates were combined,and n-hexane and propanol were added to the residue obtained byconcentrating the same under the reduced pressure. The precipitatedsolid was collected by filtration to obtain3-({4′-[5-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoicacid (635 mg).

MS (m/z): 405 [M+H]⁺

Example 94

1) N,N-dimethylformamide (7.4 mL) was added to 6-bromo-nicotinaldehyde(273 mg), tert-butyl2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]-propanoate(552 mg) and 2N aqueous sodium carbonate solution (2.2 mL), and afterreplacing the atmosphere with nitrogen, palladium chloride (dppf)methylene chloride complex (60 mg) was added to the mixture and theresulting mixture was stirred at 60° C. overnight. To the reactionmixture were added ethyl acetate and water, and the liquids wereseparated. After filtration with Celite, the organic layer wasseparated, washed with water and then with a saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 70:30) to obtain tert-butyl3-[4-(5-formylpyridin-2-yl)-phenoxy]-2,2-dimethylpropanoate (459 mg).

MS (m/z): 356 [M+H]⁺

2) By using 3,3-dibromo-1,1,1-trifluoropropan-2-one (2.02 g), andtert-butyl 3-[4-(5-formylpyridin-2-yl)-phenoxy]-2,2-dimethylpropanoate(889 mg), the procedure was carried out in the same manner as inReference example 1-1) to obtain tert-butyl2,2-dimethyl-3-{4-[5-(4-trifluoromethyl-1H-imidazol-2-yl)-pyridin-2-yl]-phenoxy}propanoateas pale yellow solid (806 mg).

MS (m/z): 462 [M+H]⁺

3) By using tert-butyl2,2-dimethyl-3-{4-[5-(4-trifluoromethyl-1H-imidazol-2-yl)pyridin-2-yl]-phenoxy}-propanoate(325 mg), the procedure was carried out in the same manner as in Example8-2) to obtain2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoicacid (167 mg).

MS (m/z):420 [M+H]⁺

4) In tetrahydrofuran (10 mL) was suspended2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoicacid (1001 mg), and the mixture was stirred at room temperature for 30minutes. 10M aqueous potassium hydroxide solution (0.25 mL) was addeddropwise to the mixture, and the mixture was stirred at room temperaturefor 2 hours. The precipitated solid was collected by filtration, washedwith tetrahydrofuran, and dried under reduced pressure to obtainpotassium2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoate(995 mg).

MS (m/z): 406 [M-K+2H]⁺

Example 95

1) In tetrahydrofuran (66 mL) was dissolved methyl5-chloropyrazine-2-carboxylate (3.3 g), and 1M diisobutylaluminumhydride/hexane solution (38.3 mL) was added dropwise to the solutionunder nitrogen atmosphere at −70° C. or lower over 10 minutes, and theresulting mixture was further stirred for 10 minutes. At −60° C. orlower, 1M diisobutylaluminum hydride/hexane solution (31.3 mL) was addeddropwise to the mixture over 20 minutes, and the mixture was furtherstirred at −70° C. or lower for 1 hour. The reaction mixture was pouredinto a saturated aqueous ammonium chloride solution, and after stirringat room temperature, filtered with Celite. The filtrate was extractedwith ethyl acetate, washed with a saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=100:0 to 80:20) to obtain 5-chloropyrazine-2-carbaldehyde (970mg).

MS (m/z): 142/144 [M+H]⁺

2) N,N-dimethylformamide (10 mL) was added to5-chloropyrazine-2-carbaldehyde (500 mg), methyl2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate(1410 mg) and 2N aqueous sodium carbonate solution (5.26 mL), and afterreplacing the atmosphere with nitrogen, palladium chloride (dppf)methylene chloride complex (143 mg) was added to the mixture and theresulting mixture was stirred at 65° C. for 2 hours. To the reactionmixture were added ethyl acetate and water, and the liquids wereseparated. After filtration with Celite, the organic layer wasseparated, washed with water and then with a saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=100:0 to 70:30) to obtain methyl3-{[5-(5-formylpyrazin-2-yl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate(855 mg).

MS (m/z): 330 [M+H]⁺

3) A mixture in which 3,3-dibromo-1,1,1-trifluoropropan-2-one (1311 mg)and sodium acetate (797 mg) were added to water (2 mL) was stirred at90° C. for 1 hour and then ice-cooled. After dissolving methyl3-{[5-(5-formylpyrazin-2-yl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate(400 mg) and 28% aqueous ammonia (8 mL) in methanol (4 mL) andtetrahydrofuran (4 mL), to the solution was added to the above-mentionedreaction solution, and the mixture was stirred at room temperature for 3hours. The reaction mixture was concentrated under reduced pressure,ethyl acetate was added to the residue and the liquids were separated.The organic layer was separated, washed with a saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=90:10 to 66:34) to obtain methyl2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}-pyridin-2-yl)oxy]propanoate(325 mg).

MS (m/z): 436 [M+H]⁺

4) Sodium hydride (60%, 35 mg) was added to an N,N-dimethylformamide (3mL) solution containing methyl2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate(320 mg) at 0° C., and the resulting mixture was stirred at the sametemperature for 1 hour. To the mixture was added2-(trimethylsilyl)ethoxymethyl chloride (195 μL), a temperature of themixture was raised to room temperature and the mixture was stirred for 1hour. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith water and then with a saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=90:10 to 80:20) to obtain a mixture (324 mg) of methyl2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoateand methyl2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-pyrazin-2-yl}pyridin-2-yl)oxy]propanoate.

MS (m/z): 566 [M+H]⁺

5) In methanol (6.4 mL) were dissolved a mixture (320 mg) of methyl2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoateand methyl2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate,and 1N aqueous sodium hydroxide solution (2.83 mL), and the resultingmixture was refluxed for 1 hour. After concentrating the mixture underreduced pressure, the residue was made acidic (pH=4) by adding 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theextract was washed with a saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to obtain amixture of2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-pyrazin-2-yl}pyridin-2-yl)oxy]propanoicacid and2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoicacid.

MS (m/z): 552 [M+H]⁺

6) In trifluoroacetic acid (3.1 mL) and water (0.31 mL) was dissolvedthe mixture of2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoicacid and2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]-propanoicacid obtained in the above-mentioned 5), and the solution was stirred atroom temperature. Acetic acid was added to the residue obtained byconcentrating the solution under reduced pressure, and the resultingmixture was concentrated under reduced pressure. Isopropyl ether wasadded to the solid residue to pulverize the same, and the pulverizedmaterial was dried to obtain2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoicacid (197 mg).

MS (m/z): 422 [M+H]⁺

Example 96

1) A mixture in which methylene chloride (10 mL) and a saturated brine(10 mL) were added to methyl3-{[5-(4-carbamimidoyl-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoateacetic acid salt (300 mg), 1-bromo-3-cyclopropylpropan-2-one (190 mg)and potassium carbonate (346 mg) was stirred at 40° C. for 5 hours. Theorganic layer was separated, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (chloroform:methanol=100:0 to 97:3)to obtain methyl3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-fluorophenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate(248 mg).

MS (m/z): 438 [M+H]⁺

2) In tetrahydrofuran (10 mL) and methanol (10 mL) was dissolved methyl3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-fluorophenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate(247 mg), and after adding 2N aqueous sodium hydroxide solution (2.8 mL)to the solution, the resulting mixture was stirred at 50° C. for 7hours. Water and acetic acid were added to the residue obtained byconcentrating the reaction mixture under reduced pressure. Theprecipitated solid was collected by filtration, washed with water anddried to obtain3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-fluorophenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoicacid (339 mg).

MS (m/z): 424 [M+H]⁺

Example 97

1) In tetrahydrofuran (11 mL) were dissolved5-bromo-4-methylpyridin-2-ol (639 mg), ethyl1-(hydroxymethyl)cyclobutanecarboxylate (538 mg) and triphenylphosphine(1.07 g), 40% diethyl azodicarboxylate-toluene solution (1.86 mL) wasadded dropwise to the solution at room temperature, and then, theresulting mixture was stirred at 60° C. for 3 hours. The reactionmixture was cooled to room temperature, concentrated under reducedpressure, and the precipitated solid was removed by filtration. Thefiltrate was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=100:0 to 90:10) to obtain ethyl1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (638mg).

MS (m/z): 328/330 [M+H]⁺

2) 1,4-Dioxane (32 mL) was added to ethyl1-{[(5-bromo-4-methylpyridin-2-yl)oxy]-methyl}cyclobutanecarboxylate(1.6 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane(1.24 g), palladium chloride (dppf) methylene chloride complex (170 mg)and potassium acetate (1.44 g), and the mixture was stirred undernitrogen atmosphere at 100° C. for 4 hours. To the reaction mixture wereadded ethyl acetate and water to extract the objective compound. Theorganic layer was washed with a saturated brine, and dried overanhydrous magnesium sulfate. After concentrating the mixture underreduced pressure, the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtain ethyl1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}methyl)cyclobutanecarboxylate(1.30 g).

MS (m/z): 376 [M+H]⁺

3) N,N-dimethylformamide (3 mL) was added to5-bromo-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(338 mg), ethyl1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}methyl)cyclobutanecarboxylate(300 mg) and palladium chloride (dppf) methylene chloride complex (33mg), and after adding 2N aqueous sodium carbonate solution (1.2 mL) tothe mixture, the atmosphere was replaced with nitrogen and the mixturewas stirred at 65° C. for 2 hours. The reaction mixture was filtered byusing Celite, and ethyl acetate and water were added to the filtrate toextract the objective compound. The organic layer was separated, washedwith a saturated brine, and dried over anhydrous magnesium sulfate.After concentrating the mixture under reduced pressure, the obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=100:0 to 90:10) to obtain ethyl1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylate(344 mg).

MS (m/z): 591 [M+H]⁺

4) Methanol (7 mL) was added to ethyl1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylate(343 mg), 1N aqueous sodium hydroxide solution (2.9 mL) was furtheradded to the mixture and the resulting mixture was refluxed for 1 hour.Methanol was distilled off under reduced pressure, and the residue wasneutralized by 1N hydrochloric acid. The mixture was extracted withethyl acetate, the organic layer was washed with a saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to obtain1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylicacid.

MS (m/z): 563[M+H]⁺

5) In trifluoroacetic acid (3.3 mL) and water (0.33 mL) was dissolved1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylicacid (327 mg), and the solution was stirred at room temperature for 60hours. The reaction mixture was concentrated under reduced pressure,subjected to azeotropic distillation with acetic acid, and isopropylether was added to the obtained residue. The precipitated solid wascollected by filtration and dried under reduced pressure to obtain1-[({4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylicacid (217 mg).

MS (m/z): 433 [M+H]⁺

Example 98

1) N,N-dimethylformamide (5 mL) was added to2-(4-bromo-2-fluorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(293 mg), ethyl1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}methyl)cyclobutanecarboxylate(250 mg) and palladium chloride (dppf) methylene chloride complex (28mg), and after adding 2N aqueous sodium carbonate solution (1 mL) to themixture, the atmosphere was replaced with nitrogen and the mixture wasstirred at 65° C. for 3 hours. To the reaction mixture were added ethylacetate and water to extract the objective compound. The organic layerwas washed with a saturated brine, and dried over anhydrous magnesiumsulfate. After concentrating the mixture under reduced pressure, theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=100:0 to 80:20) to obtain ethyl1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate(316 mg).

MS (m/z): 608 [M+H]⁺

2) Methanol (6.3 mL) and 1N aqueous sodium hydroxide solution (2.6 mL)were added to ethyl1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate(315 mg) and the mixture was refluxed for 1 hour. Methanol was distilledoff under reduced pressure, and the residue was neutralized by 1Nhydrochloric acid. The mixture was extracted with ethyl acetate, theorganic layer was washed with a saturated brine, and dried overanhydrous magnesium sulfate. After concentrating the mixture underreduced pressure, the obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 95:5) to obtain1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylicacid (308 mg).

MS (m/z): 580 [M+H]⁺

3) In trifluoroacetic acid (3.0 mL) and water (0.3 mL) was dissolved1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylicacid (299 mg), and the solution was stirred at 50° C. for 3 hours. Thereaction mixture was concentrated under reduced pressure, the residuewas made a pH=4 with a saturated aqueous sodium hydrogen carbonatesolution and 1N hydrochloric acid, extracted with ethyl acetate, and theorganic layer was washed with a saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, concentrated under reducedpressure, and isopropyl ether was added to the obtained residue. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain1-{[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylicacid (200 mg).

MS (m/z): 450 [M+H]⁺

Example 99

1) In N,N-dimethylformamide (24 mL) was dissolved5-bromo-3-chloropyridine-2-carboxylic acid (2.36 g),1-hydroxybenzotriazole (2.2 g) and3-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.87 g),N,O-dimethylhydroxylamine hydrochloride (1.27 g) and triethylamine (1.95mL) was added to the solution, and the resulting mixture was stirred atroom temperature for 20 hours. Water was added to the obtained residue,extracted with ethyl acetate, and the organic layer was washed withwater and then with a saturated brine. After drying the mixture overanhydrous magnesium sulfate, the mixture was concentrated under reducedpressure to obtain5-bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.67 g).

MS (m/z): 279/281/283 [M+H]⁺

2) In tetrahydrofuran (27 mL) was dissolved5-bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.66 g), themixture was cooled under nitrogen atmosphere at −70° C. or lower, and atetrahydrofuran (5 mL) suspension of lithium aluminum hydride (180 mg)was added dropwise to the mixture. The mixture was stirred at −70° C. orlower for 2 hours, then, water (10 mL) and a saturated brine (10 mL)were added dropwise to the mixture. A temperature of the mixture wasraised to room temperature, the mixture was extracted with ethylacetate, and the organic layer was washed with water and a saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate,concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10)to obtain a mixture of an aldehyde compound and an aldehyde equivalent(2.1 g). To water (36 mL) were added3,3-dibromo-1,1,1-trifluoropropan-2-one (6.61 g) and sodium acetate(4.02 g) and the mixture was stirred at 95° C. for 30 minutes. Anaqueous solution obtained by ice-cooling the mixture was added to amixture comprising the previously obtained mixture of thealdehyde/aldehyde equivalent (1.8 g), 28% aqueous ammonia (18 mL) andmethanol (36 mL) at room temperature, and the resulting mixture wasstirred at room temperature for 17 hours. The reaction mixture wasconcentrated, the residue was extracted with ethyl acetate, and theorganic layer was washed with a saturated brine, and then, dried overanhydrous magnesium sulfate. After concentrating the mixture underreduced pressure, the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=80:20), and the obtained solidwas collected by filtration, washed with isopropyl ether and dried toobtain 5-bromo-3-chloro-2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine(935 mg).

MS (m/z): 326/328/330 [M+H]⁺

3) In N,N-dimethylformamide (13 mL) was dissolved5-bromo-3-chloro-2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (1.27g), 60% sodium hydride (187 mg) was added to the solution underice-cooling, and after raising the mixture to room temperature, themixture was stirred for 1 hour. The reaction mixture was ice-cooled,2-(trimethylsilyl)ethoxymethyl chloride (1.03 mL) was added to themixture, and after raising the mixture to room temperature, the mixturewas stirred for 1 hour. Water was added to the reaction mixture, themixture was extracted with ethyl acetate, and the organic layer waswashed with water and a saturated brine, and dried over anhydrousmagnesium sulfate. After concentrating the mixture under reducedpressure, the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtain5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(1.56 g).

MS (m/z): 458/460/462 [M+H]⁺

4) N,N-dimethylformamide (3 mL) was added to5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(365 mg), ethyl1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-oxy}methyl)cyclobutanecarboxylate(300 mg) and palladium chloride (dppf) methylene chloride complex (33mg), and after adding 2N aqueous sodium carbonate solution (1.2 mL) tothe mixture, the atmosphere was replaced with nitrogen and the mixturewas stirred at 65° C. for 2 hours. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated brine, concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylate(318 mg).

MS (m/z): 625/627 [M+H]⁺

5) Methanol (7 mL) and 1N aqueous sodium hydroxide solution (2.6 mL)were added to ethyl1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylate(327 mg), and the mixture was refluxed for 1 hour. Methanol wasdistilled off under reduced pressure, and the residue was neutralized by1N hydrochloric acid. The mixture was extracted with ethyl acetate, theorganic layer was washed with a saturated brine, and dried overanhydrous magnesium sulfate. The mixture was concentrated under reducedpressure to obtain1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylicacid.

MS (m/z): 597/599 [M+H]⁺

6) In trifluoroacetic acid (3.1 mL) and water (0.3 mL) was dissolved1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylicacid (312 mg), and the mixture was allowed to stand at room temperaturefor 60 hours. The reaction mixture was concentrated under reducedpressure, subjected to azeotropic distillation with acetic acid,isopropyl ether was added to the obtained residue, and the precipitatedsolid was collected by filtration and dried under reduced pressure toobtain1-[({5′-chloro-4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylicacid (151 mg).

MS (m/z): 467/469 [M+H]⁺

Example 100

1) In tetrahydrofuran (26 mL) was dissolved 5-bromo-4-methylpyridin-2-ol(1.3 g), methyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.08 g) andtriphenylphosphine (2.72 g), and 40% diethyl azodicarboxylate-toluenesolution (4.72 mL) was added dropwise to the solution at 0° C. Themixture was stirred at 70° C. for 4 hours. The reaction mixture wascooled to room temperature, water and ethyl acetate were added to themixture, and the organic layer was washed with a saturated brine anddried over anhydrous sodium sulfate. After concentrating the mixtureunder reduced pressure, the obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=99:1 to 99:5) to obtainmethyl1-{[(5-bromo-4-methylpyridin-2-yl)oxy]-methyl}cyclopropanecarboxylate(2.08 g).

MS (m/z): 300/302 [M+H]⁺

2) 1,4-Dioxane (20 mL) was added to methyl1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylate(1.01 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane(1.03 g), palladium chloride (dppf) methylene chloride complex (71 mg)and potassium acetate (994 mg), and the mixture was stirred undernitrogen atmosphere at 100° C. for 3 hours. To the reaction mixture wereadded ethyl acetate and water to extract the objective compound. Theorganic layer was washed with a saturated brine, and dried overanhydrous magnesium sulfate. After concentrating the mixture underreduced pressure, the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=95:5 to 80:20) to obtain methyl1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}methyl)cyclopropanecarboxylate(1.08 g).

MS (m/z): 348 [M+H]⁺

3) N,N-dimethylformamide (11 mL) was added to2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(220 mg), methyl1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}-methyl)cyclopropanecarboxylate(201 mg), and palladium chloride (dppf) methylene chloride complex (39mg), and after adding 2N aqueous sodium carbonate solution (0.72 mL) tothe mixture, the atmosphere was replaced with nitrogen and the mixturewas stirred at 65° C. for 2 hours. To the reaction mixture were addedethyl acetate and water to extract the objective compound, and theorganic layer was washed with a saturated brine, and dried overanhydrous sodium sulfate. After concentrating the mixture under reducedpressure, the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=95:5 to 80:20) to obtain methyl1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylate(237 mg).

MS (m/z): 596/598 [M+H]⁺

4) In methanol (7 mL) and tetrahydrofuran (7 mL) was dissolved methyl1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylate(236 mg), 2N aqueous sodium hydroxide solution (1.98 mL) was added tothe solution and the resulting mixture was stirred at 50° C. for 4hours. The reaction mixture was concentrated under reduced pressure, andacetic acid and ethyl acetate were added to the residue. The organiclayer was separated, washed with a saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtain1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylicacid (221 mg).

MS (m/z): 582/584 [M+H]⁺

5) In trifluoroacetic acid (5.0 mL) and water (0.5 mL) was dissolved1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylicacid (219 mg), and the solution was stirred at room temperature for 5hours. The reaction mixture was concentrated under reduced pressure, asmall amount of tetrahydrofuran was added to the residue, and themixture was neutralized by 1N aqueous sodium hydroxide solution. Severaldrops of acetic acid was added to the mixture, the mixture was extractedwith ethyl acetate, washed with a saturated brine, and the organic layerwas separated and concentrated under reduced pressure. Isopropyl etherwas added to the obtained residue, and the precipitated solid wascollected by filtration and dried under reduced pressure to obtain1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylicacid (95 mg).

MS (m/z): 452/454 [M+H]⁺

Example 101

1) N,N-dimethylformamide (3.3 mL) was added to2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(200 mg), ethyl1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}-methyl)cyclobutanecarboxylate(164 mg) and palladium chloride (dppf) methylene chloride complex (18mg), and after adding 2N aqueous sodium carbonate solution (0.66 mL) tothe mixture, the atmosphere was replaced with nitrogen and the mixturewas stirred at 65° C. for 3 hours. To the reaction mixture were addedethyl acetate and water, and the liquids were separated. The organiclayer was separated, washed with a saturated brine, and the residueobtained by concentrating the mixture under reduced pressure waspurified by silica gel column chromatography (n-hexane:ethylacetate=100:0 to 80:20) to obtain ethyl1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate(214 mg).

MS (m/z): 624/626 [M+H]⁺

2) Methanol (4.3 mL) and 1N aqueous sodium hydroxide solution (1.7 mL)were added to ethyl1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate(213 mg), and the mixture was refluxed for 1 hour. Methanol wasdistilled off under reduced pressure, and the residue was neutralized by1N hydrochloric acid. The mixture was extracted with ethyl acetate, theorganic layer was washed with a saturated brine, and dried overanhydrous magnesium sulfate. After concentrating the mixture underreduced pressure, the obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 95:5) to obtain1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylicacid (205 mg).

MS (m/z): 596/598 [M+H]⁺

3) In trifluoroacetic acid (2.0 mL) and water (0.2 mL) was dissolved1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylicacid (202 mg), and the solution was stirred at 50° C. for 3 hours. Thereaction mixture was concentrated under reduced pressure, the pH of theresidue was made 4 with a saturated aqueous sodium hydrogen carbonatesolution and 1N hydrochloric acid, and the mixture was extracted withethyl acetate. The extract was washed with a saturated brine, theorganic layer was separated and concentrated under reduced pressure.Isopropyl ether was added to the obtained residue, and the precipitatedsolid was collected by filtration and dried under reduced pressure toobtain1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylicacid (137 mg).

MS (m/z): 466/468 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Examples 1 to 101.

TABLE 10 Exam- Starting Starting ple substance 1 substance 2 102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

Exam- MS ple Product (m/z) 102

475 [M + H]⁺ 103

422 [M + H]⁺ 104

408 [M + H]⁺ 105

441/443 [M + H]⁺ 106

408 [M + H]⁺ 107

439 [M + H]⁺ 108

406 [M + H]⁺ 109

420 [M + H]⁺ 110

438 [M + H]⁺ 111

464 [M + H]⁺ 112

455/457 [M + H]⁺ 113

445 [M + H]⁺ 114

435 [M + H]⁺ 115

480 [M + H]⁺ 116

471 [M + H]⁺ 117

409 [M + H]⁺ 118

407 [M + H]⁺ 119

426 [M + H]⁺ 120

442 [M + H]⁺ 121

440/442 [M + H]⁺ 122

470 [M + H]⁺ 123

484 [M + H]⁺ 124

488 [M + H]⁺ 125

504/506 [M + H]⁺ 126

422 [M + H]⁺ 127

449 [M + H]⁺ 128

448 [M + H]⁺ 129

450 [M + H]⁺ 130

488 [M + H]⁺ 131

460 [M + H]⁺ 132

419 [M + H]⁺ 133

436 [M + H]⁺ 134

466 [M + H]⁺ 135

505/507 [M + H]⁺ 136

437 [M + H]⁺ 137

451 [M + H]⁺ 138

467 [M + H]⁺ 139

453/455 [M + H]⁺ 140

482/484 [M + H]⁺ 141

425 [M + H]⁺ 142

441/443 [M + H]⁺ 143

466 [M + H]⁺ 144

478 [M + H]⁺ 145

421 [M + H]⁺ 146

463 [M + H]⁺ 147

434 [M + H]⁺ 148

472 [M + H]⁺

Reference Example 1

1) To water (15 mL) were added 3,3-dibromo-1,1,1-trifluoropropan-2-one(4.05 g) and sodium acetate (2.46 g), and the mixture was stirred at 95°C. for 30 minutes. The solution obtained by ice-cooling was added to asolution in which 6-bromo-nicotinaldehyde (1.86 g) was dissolved in 28%aqueous ammonia (20 mL) and methanol (60 mL) under ice-cooling, and themixture was stirred overnight while the temperature of the mixture wasgradually raised to room temperature. The reaction mixture wasconcentrated under reduced pressure, then, water and ethyl acetate wereadded thereto and the liquids were separated, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. To the obtained solid residue was added ether to pulverize thesame, and the solid was collected by filtration and dried to obtain2-bromo-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (1.25 g).

MS (m/z): 292/294 [M+H]⁺

2) 60% Sodium hydride (2.62 g) was added to a solution of2-bromo-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (13.65 g)dissolved in N,N-dimethylformamide (150 mL) under nitrogen atmosphereand under ice-cooling, and the mixture was stirred for 30 minutes. Tothe mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (12.4 mL)under ice-cooling, and the mixture was stirred overnight while thetemperature of the mixture was gradually raised to room temperature. Tothe reaction mixture was added a saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and the aqueous layer at thistime was extracted with ethyl acetate. The organic layers were combinedand dried, and the residue obtained by concentrating the reactionmixture under reduced pressure was purified by silica gel columnchromatography (n-hexane:ethyl acetate) to obtain2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(9.42 g).

MS (m/z): 422/424 [M+H]⁺

3) Palladium chloride (dppf) methylene chloride complex (0.193 g) wasadded to a mixture of2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(1.0 g), (4-benzyloxyphenyl)boronic acid (1.08 g), 2M aqueous sodiumcarbonate solution (4.74 mL) and N,N-dimethylformamide (18.9 mL) undernitrogen atmosphere, and the mixture was stirred at 65° C. undernitrogen atmosphere overnight. To the mixture were added water and ethylacetate, and then, insoluble material was removed by filtration usingCelite. The organic layer was separated, washed with saline, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=88:12 to 80:20) to obtain2-[4-(benzyloxy)phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(1.038 g).

MS (m/z): 526 [M+H]⁺

4) In methanol (8 mL) and tetrahydrofuran (6 mL) was dissolved2-[4-(benzyloxy)phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine(0.77 g), and after adding palladium carbon (0.154 g) under nitrogenatmosphere, the atmosphere was replaced by hydrogen, and the mixture wasstirred at room temperature for 5 hours. Insoluble material was filteredoff by using a membrane filter, and the filtrate was concentrated underreduced pressure. The concentrate was diluted with methanol, activatedcharcoal was added thereto, and the mixture was filtered by usingCelite. The filtrate was concentrated under reduced pressure andcrystallized to obtain4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol(0.612 g).

MS (m/z): 436 [M+H]⁺

Reference Example 2

1) 40% Diethyl azodicarboxylate-toluene solution (9.54 mL) was added toa tetrahydrofuran (40 mL) solution containing 4-bromophenol (2.0 g),methyl hydroxypivalate (2.77 g) and triphenylphosphine (5.49 g), and themixture was stirred at 70° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure, and purified by silica gel columnchromatography (n-hexane:ethyl acetate=90:10) to obtain methyl3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g).

MS (m/z): 287/289 [M+H]⁺

2) To 1,4-dioxane (60 mL) were added methyl3-(4-bromophenoxy)-2,2-dimethylpropanoate (4.68 g),bis(pinacolato)diboron (5.17 g), palladium chloride (dppf) methylenechloride complex (399 mg) and potassium acetate (4.80 g), and themixture was stirred at 80° C. under nitrogen atmosphere overnight. Thereaction mixture was passed through a short column filled with silicagel and NH-silica gel and washed with ethyl acetate. The residueobtained by concentrating the filtrate under reduced pressure waspurified by silica gel column chromatography (n-hexane:ethylacetate=93:7 to 75:25) to obtain methyl2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]propanoate(4.93 g).

MS (m/z): 335 [M+H]⁺

3) To N,N-dimethylformamide (140 mL) were added methyl2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]propanoate(8.6 g), 2-chloropyridin-5-cyanide (3.0 g), palladium chloride (dppf)complex (788 mg) and 2N aqueous sodium carbonate solution (32 mL), andthe mixture was stirred at 65° C. under nitrogen atmosphere overnight.After cooling the reaction mixture to room temperature, water and ethylacetate were added to the mixture and the mixture was filtered by usingCelite. The organic layer was separated, washed with water, dried overanhydrous sodium sulfate, and the residue obtained by concentrating thereaction mixture under reduced pressure was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=95:5 to 70:30) to obtainmethyl 3-[4-(5-cyanopyridin-2-yl)phenoxy]-2,2-dimethylpropanoate (6.0g).

MS (m/z): 311 [M+H]⁺

4) 50% Aqueous hydroxylamine solution (40 g) was added to a methanol(100 mL) and tetrahydrofuran (100 mL) solution containing methyl3-[4-(5-cyanopyridin-2-yl)phenoxy]-2,2-dimethylpropanoate (6.0 g), andthe mixture was stirred at 80° C. for 4 hours. After cooling thereaction mixture to room temperature, the mixture was concentrated underreduced pressure. To the obtained residue were added ethyl acetate andwater, and the liquids were separated. The organic layer was separated,washed with water, and dried over anhydrous sodium sulfate. Ether wasadded to the solid residue obtained by concentrating the mixture underreduced pressure to pulverize the same, and the solid was collected byfiltration and dried to obtain methyl3-(4-{5-[amino(hydroxyimino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate(5.8 g).

MS (m/z): 344 [M+H]⁺

5) In acetic acid (60 mL) was dissolved methyl3-(4-{5-[amino(hydroxyimino)methyl]-pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate(5.8 g), acetic anhydride (4 mL) was added to the solution and themixture was stirred at room temperature for 2 hours. To the residueobtained by concentrating the mixture under reduced pressure were addedmethanol (300 mL) and tetrahydrofuran (70 mL), and 10% palladium carbon(1.2 g) was added to the mixture under nitrogen atmosphere. Theatmosphere of the reaction mixture was made hydrogen atmosphere, and themixture was stirred at room temperature for 2 hours. After replacing theatmosphere with nitrogen, the mixture was filtered using Celite. Thefiltrate was concentrated under reduced pressure, ether was added to theobtained residue to pulverize the solid, and the solid was collected byfiltration and dried to obtain methyl3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoateacetate (6.11 g).

MS (m/z): 328 [M+H]⁺

Reference Example 3

1) By using 4-bromobenzaldehyde (1.0 g), the procedure was carried outin the same manner as in Reference example 1-1) to obtain2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (1.22 g).

MS (m/z): 291/293 [M+H]⁺

2) By using 2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (1.22 g),the procedure was carried out in the same manner as in Reference example1-2) to obtain2-(4-bromophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(1.63 g).

MS (m/z): 421/423 [M+H]⁺

Reference Example 4

1) By using 3-bromo-6-hydroxypyridine (3.57 g), the procedure wascarried out in the same manner as in Reference example 2-1) to obtainmethyl 3-[(5-bromopyridin-2-yl)oxy]-2,2-dimethylpropanoate (4.83 g).

MS (m/z): 288/290 [M+H]⁺

2) By using methyl 3-[(5-bromopyridin-2-yl)oxy]-2,2-dimethylpropanoate(4.82 g), the procedure was carried out in the same manner as inReference example 2-2) to obtain methyl2,2-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)pyridin-2-yl]oxy}propanoate(6.16 g).

MS (m/z): 336 [M+H]⁺

Reference Example 5

1) By using 4-bromo-2-fluorophenol (2.0 g), the procedure was carriedout in the same manner as in Reference example 2-1) to obtain methyl3-(4-bromo-2-fluorophenoxy)-2,2-dimethylpropanoate (3.11 g).

MS (m/z): 305/307 [M+H]⁺

2) By using methyl 3-(4-bromo-2-fluorophenoxy)-2,2-dimethylpropanoate(3.1 g), the procedure was carried out in the same manner as inReference example 2-2) to obtain methyl3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]-2,2-dimethylpropanoate(1.912 g).

MS (m/z): 370 [M+H]⁺

Reference Example 6

1) In N,N-dimethylformamide (40 mL) was dissolved4-bromo-2-methyl-phenol (1.87 g), potassium carbonate (4.15 g) andbenzyl bromide (1.3 mL) were added to the solution, and the mixture wasstirred at room temperature for 2 hours. To the reaction mixture wereadded water and ethyl acetate, and the liquids were separated. Theorganic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=98:2 to 95:5) to obtain1-benzyloxy-4-bromo-2-methylbenzene (2.73 g).

NMR (400 MHz, d₆-DMSO) σ: 2.19 (s, 3H), 5.11 (s, 2H), 6.97 (d, J=8 Hz,1H), 7.29-7.46 (m, 7H)

2) To 1,4-dioxane (50 mL) were added 1-benzyloxy-4-bromo-2-methylbenzene(2.73 g), tris(dibenzylideneacetone)dipalladium (0.18 g),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.19 g),potassium acetate (2.90 g) and bis(pinacolato)diboron (7.52 g), and themixture was stirred at 110° C. under nitrogen atmosphere overnight.After cooling the reaction mixture to room temperature, insolublematerial was removed by filtration using Celite, and washed with ethylacetate. The filtrate was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=98:2 to 95:5) to obtain2-(4-benzyloxy-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.22 g).

MS (m/z): 325 [M+H]⁺

3) By using2-(4-benzyloxy-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.08 g) and2-bromo-5-[4-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-2-yl]pyridine(0.7 g), the procedure was carried out in the same manner as inReference example 1-3) to obtain2-[[2-[6-(4-benzyloxy-3-methylphenyl)-3-pyridyl]-4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyltrimethylsilane(0.892 g).

MS (m/z): 540 [M+H]⁺

4) By using2-[[2-[6-(4-benzyloxy-3-methylphenyl)-3-pyridyl]-4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyltrimethylsilane(0.89 g), the procedure was carried out in the same manner as inReference example 1-4) to obtain2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenol(0.656 g).

MS (m/z):450 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Reference example 6.

TABLE 11 Reference MS example Starting substance Product (m/z)  7

450 [M + H]⁺  8

437 [M + H]⁺  9

451 [M + H]⁺ 10

437 [M + H]⁺

Reference Example 11

1) By using 4-bromophenol (1.33 g) and methyl1-(hydroxymethyl)cyclopropane carboxylate (663 mg), the procedure wascarried out in the same manner as in Reference example 2-1) to obtainmethyl 1-[(4-bromophenoxy)methyl]cyclopropane carboxylate (1.03 g).

MS (m/z): 302/304 [M+H]⁺

2) By using methyl 1-[(4-bromophenoxy)methyl]cyclopropane carboxylate(1.0 g), the procedure was carried out in the same manner as inReference example 2-2) to obtain methyl1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]methyl]cyclopropanecarboxylate (930 mg).

MS (m/z): 350 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Reference example 11.

TABLE 12 Refer- ence exam- Starting sub- Starting sub- MS ple stance 1stance 2 Product (m/z) 12

370 [M + H]⁺ 13

458 [M + H]⁺ 14

375 [M + H]⁺ 15

347 [M + H]⁺ 16

350 [M + H]⁺ 17

350 [M + H]⁺ 18

371 [M + H]⁺ 19

354 [M + H]⁺

Reference Example 20

1) In N,N-dimethylformamide (10 mL) were dissolved5-bromo-2-chloropyridine (1000 mg) and tert-butyl3-hydroxy-2,2-dimethylpropanoate (991 mg), and 60% sodium hydride (248mg) was added to the solution under ice-cooling. The reaction mixturewas stirred at room temperature for 6 hours, at 50° C. for 1 hour and 45minutes, and then, at room temperature overnight. Water was added to thereaction mixture under ice-cooling, and the mixture was extracted withether. The organic layer was separated, washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtaintert-butyl 3-(5-bromopyrimidin-2-yl)oxy-2,2-dimethylpropanoate (1.048g).

MS (m/z): 331/333 [M+H]⁺

2) By using tert-butyl3-(5-bromopyrimidin-2-yl)oxy-2,2-dimethylpropanoate (1.045 g), theprocedure was carried out in the same manner as in Reference example2-2) to obtain tert-butyl2,2-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)pyrimidin-2-yl]oxopropanoate(795 mg).

MS (m/z): 379 [M+H]⁺

Reference Example 21

1) In tetrahydrofuran (40 mL) was dissolved methyl3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g), 2N aqueous sodiumhydroxide solution (10 mL) was added to the solution, and the mixturewas stirred at room temperature overnight. After adding methanol (10 mL)to the mixture, the resulting mixture was refluxed for 3 hours. To theresidue obtained by concentrating the reaction mixture under reducedpressure were added ethyl acetate and 1N hydrochloric acid, and theliquids were separated. The organic layer was separated, washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to obtain3-(4-bromophenoxy)-2,2-dimethylpropanoic acid (2.886 g).

MS (m/z): 273/275 [M+H]⁺

2) In methylene chloride (10 mL) was dissolved3-(4-bromophenoxy)-2,2-dimethylpropanoic acid (500 mg), oxalyl chloride(240 μL) and N,N-dimethylformamide (1 drop) were added dropwise to thesolution under ice-cooling, and the mixture was stirred at roomtemperature for 1 hour. The residue obtained by concentrating thereaction mixture under reduced pressure was dissolved in acetonitrile (5mL), and an n-hexane solution (1.83 mL) containing 2M(trimethylsilyl)diazomethane was added dropwise to the mixture underice-cooling. Then, the reaction mixture was stirred under ice-coolingfor 1 hour and at room temperature overnight. To the residue obtained byconcentrating the reaction mixture under reduced pressure were addedethyl acetate and a saturated aqueous sodium bicarbonate solution, andthe liquids were separated. The organic layer was separated, washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was dissolved in ethanol(20 mL), triethylamine (2.04 mL) and silver benzoate (168 mg) were addedto the solution, and the mixture was refluxed under nitrogen atmospherefor 2 hours. Insoluble material was filtered off using a membranefilter, the filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=95:5 to 90:10) to obtain ethyl4-(4-bromophenoxy)-3,3-dimethylbutanoate (397 mg).

MS (m/z): 315/317 [M+H]⁺

3) By using ethyl 4-(4-bromophenoxy)-3,3-dimethylbutanoate (396 mg), theprocedure was carried out in the same manner as in Reference example2-2) to obtain ethyl3,3-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]butanoate(190 mg).

MS (m/z): 363 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Reference example 1.

TABLE 13 Refer- ence exam- Starting Starting MS ple substance 1substance 2 Product (m/z) 22

422/424 [M + H]⁺ 23

472/474 [M + H]⁺ 24

439/441 [M + H]⁺ 25

392/394 [M + H]⁺ 26

435/437 [M + H]⁺ 27

457/459 [M + H]⁺ 28

439/441 [M + H]⁺ 29

455/457/ 459 [M + H]⁺ 30

436/438 [M + H]⁺ 31

439/441 [M + H]⁺

Reference Example 32

1) To tetrahydrofuran (50 mL) were added methyl2,2-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)pyridin-2-yl]oxy}propanoate(3000 mg), 2-bromopyridin-5-cyanide (1965.4 mg), palladium acetate(100.5 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (367 mg) andpotassium phosphate (3799.4 mg), and the mixture was stirred at 50° C.under nitrogen atmosphere for 2 days. To the reaction mixture was addedsaturated brine, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with water, dried over anhydroussodium sulfate, and the residue obtained by concentrating the reactionmixture under reduced pressure was purified by silica gel columnchromatography (n-hexane:ethyl acetate=85:15 to 65:35) to obtain methyl3-{[5-(5-cyanopyridin-2-yl)pyridin-2-yl]oxy}-2,2-dimethylpropanoate (720mg).

MS (m/z): 312 [M+H]⁺

2) By using methyl3-{[5-(5-cyanopyridin-2-yl)pyridin-2-yl]oxy}-2,2-dimethylpropanoate (718mg), the procedure was carried out in the same manner as in Referenceexample 2-4) and 2-5) to obtain methyl3-[(5-{5-[amino(imino)methyl]pyridin-2-yl}-pyridin-2-yl)oxy]-2,2-dimethylpropanoateacetate (467 mg).

MS (m/z): 329 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Reference example 32.

TABLE 14 Refer- ence exam- Starting Starting ple substance 1 substance 233

34

35

36

37

38

39

40

Refer- ence exam- MS ple Product (m/z) 33

343 [M + H]⁺ 34

356 [M + H]⁺ 35

342 [M + H]⁺ 36

342 [M + H]⁺ 37

346 [M + H]⁺ 38

329 [M + H]⁺ 39

347 [M + H]⁺ 40

346 [M + H]⁺

Reference Example 41

1) By using 2,6-dichloro-4-methylpyridin-3-carbonitrile (2000 mg) andmethyl2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenoxy]propanoate(3573.9 mg), the procedure was carried out in the same manner as inReference example 1-3) to obtain methyl3-[4-(6-chloro-5-cyano-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate(2697 mg).

MS (m/z): 359/361 [M+H]⁺

2) By using methyl3-[4-(6-chloro-5-cyano-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate(2660 mg), the procedure was carried out in the same manner as inReference example 2-4) to obtain methyl3-{4-[6-chloro-5-(N-hydroxycarbamimidoyl)-4-methylpyridin-2-yl]phenoxy}-2,2-dimethylpropanoate(2977 mg).

MS (m/z): 392/394 [M+H]⁺

3) By using methyl3-{4-[6-chloro-5-(N-hydroxycarbamimidoyl)-4-methylpyridin-2-yl]phenoxy}-2,2-dimethylpropanoate(2900 mg), the procedure was carried out in the same manner as inReference example 2-5) to obtain methyl3-[4-(5-carbamimidoyl-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate(2300 mg).

MS (m/z): 342 [M+H]⁺

Reference Example 42

By using2-(4-bromophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazole(869 mg), the procedure was carried out in the same manner as inReference example 2-2) to obtain2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl)phenyl]-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(724.9 mg).

MS (m/z): 469 [M+H]⁺

By using the corresponding starting materials, the following compoundswere synthesized in the same manner as in Reference example 42.

TABLE 15 Reference MS example Starting substance Product (m/z) 43

487 [M + H]⁺ 44

470 [M + H]⁺

Reference Example 45

By using 5-chloropyrazin-2-ol (700 mg) and tert-butyl hydroxypivalate(1402 mg), the procedure was carried out in the same manner as inExample 1-1) to obtain tert-butyl3[(5-chloropyrazin-2-yl)oxy]-2,2-dimethylpropanoate (1294.5 mg).

MS (m/z): 287/289 [M+H]⁺

Reference Example 46

1) A mixture of 2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (3g), benzyl bromide (3.52 g), potassium carbonate (2.85 g) andN,N-dimethylformamide (30 mL) was stirred at room temperature overnight.To the reaction mixture were added water and ether, and the liquids wereseparated. The organic layer was separated, washed with water and thenwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was dissolvedin toluene, and purified by silica gel column chromatography(n-hexane:ethyl acetate=100:0 to 70:30) to obtain1-benzyl-2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole (3.40 g).

MS (m/z): 381/383 [M+H]⁺

Reference Example 47

By using 5-bromo-3-fluoropyridin-2-ol (0.96 g), the procedure wascarried out in the same manner as in Example 1-1) to obtain methyl3-[(5-bromo-3-fluoropyridin-2-yl)oxy]-2,2-dimethylpropanoate (1.35 g).

MS (m/z): 306/308 [M+H]⁺

Reference Example 48

1) In ethanol (10 mL) was dissolved2-bromo-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyridine (500 mg), 2Naqueous sodium hydroxide solution was added to the solution, and themixture was stirred at 70° C. overnight. The reaction mixture wasconcentrated under reduced pressure, and 1N aqueous citric acid solutionwas added thereto. The precipitated solid substance was collected byfiltration, washed with water, and then, with ether, and dried to obtain2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylic acid (722 mg).

MS (m/z): 268/270 [M+H]⁺

2) To an N,N-dimethylacetamide solution containing2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylic acid (4.99 g) anddiisopropylethylamine (4.21 mL) was added benzyl bromide (3.81 g) underice-cooling, after stirring the mixture for 5 minutes, the temperatureof the mixture was raised to room temperature and the mixture wasstirred overnight. Water was added to the reaction mixture underice-cooling, and the precipitated solid was collected by filtration,washed with water and n-hexane, and dried to obtain benzyl2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylate (6.01 g).

MS (m/z): 358/360 [M+H]⁺

3) By using benzyl 2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylate(5.5 g), the procedure was carried out in the same manner as inReference example 1-2) to obtain benzyl2-(6-bromopyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]-1H-imidazol-4-carboxylate(2.97 g).

MS (m/z): 488/490 [M+H]⁺

4) By using benzyl2-(6-bromopyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]-1H-imidazol-4-carboxylate(6.69 g) and2-{4-[(4-methoxybenzyl)oxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(6.04 g), the procedure was carried out in the same manner as inReference example 1-3) to obtain benzyl2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}-pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-carboxylate(6.54 g).

MS (m/z): 622 [M+H]⁺

5) To a tetrahydrofuran (40 mL) suspension of lithium aluminum hydride(0.24 g) was added dropwise a tetrahydrofuran (30 mL) solution of benzyl2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-carboxylate(2 g) under ice-cooling. After stirring for 30 minutes, sodium sulfate(720 mg) and water (0.48 mL) were added to the mixture. The mixture wasstirred at room temperature for 1 hour, and filtered. The filtrate wasconcentrated under reduced pressure, the obtained residue was pulverizedby adding ether, and collected by filtration to obtain[2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl]methanol.

MS (m/z): 518 [M+H]⁺

6) In methylene chloride (100 mL) was dissolved[2-(6-{4-[(4-methoxybenzyl)oxy]-phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl]methanolobtained in the above-mentioned 5), manganese dioxide (5.59 g) was addedto the solution, and the mixture was stirred at room temperature for 2days. The reaction mixture was filtered and then purified by silica gelcolumn chromatography (chloroform to chloroform:methanol=97:3) to obtain2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-carbaldehyde(1.25 g).

MS (m/z): 516 [M+H]⁺

7) To a tetrahydrofuran (70 mL) solution containingdibromodifluoromethane (5.09 g) was added dropwise hexamethyl phosphorictriamide (8.81 mL) at −78° C. The temperature of the mixture wasreturned to room temperature, and the mixture was stirred for 30minutes. The mixture was cooled to −78° C., and a tetrahydrofuran (20mL) solution of2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-carbaldehyde(1.25 g) was added dropwise thereto. The temperature of the mixture wasreturned to room temperature, and the mixture was stirred for 3 hours.To the mixture were added ethyl acetate, water and a saturated aqueoussodium bicarbonate solution, and the liquids were separated. The organiclayer was separated, washed with saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=85:15 to 55:45) to obtain5-[4-(2,2-difluoroethenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-2-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine(0.84 g).

MS (m/z): 550 [M+H]⁺

8) In ethanol (50 mL) and tetrahydrofuran (20 mL) was dissolved5-[4-(2,2-difluoroethenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-2-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine(0.84 g), 10% palladium-carbon (50% water contained, 395 mg) was addedto the solution, and the mixture was stirred under hydrogen atmospherefor 24 hours. The reaction mixture was filtered by using a membranefilter, the filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to obtain4-{5-[4-(2,2-difluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol(373 mg).

MS (m/z): 432 [M+H]⁺

Experimental Example 1 DGAT1 Inhibitory Activity <Experimental Method>(1) Cloning of Human DGAT1 Gene and Preparation of RecombinantBaculovirus

Human DGAT1 gene was obtained by using a human cDNA library as atemplate, and amplifying a base sequence (245-1711 in Genbank AccessionNo. NM_012079) which encodes DGAT1 by PCR reaction.

The obtained human DGAT1 gene was subjected to ligation to plasmidpVL1392 (BD Biosciences) to prepare expression plasmid pVL1392-DGAT1.Further, by using BD BaculoGold Baculovirus Expression vector system (BDBiosciences), recombinant baculovirus was prepared.

(2) Preparation of Microsome of Human DGAT1 Enzyme HighlyExpressed-Insect Cells

Preparation of human DGAT1 enzyme was carried out by infecting therecombinant baculovirus obtained in the previous item with expresSF+®insect cells (available from NOSAN Corporation). The recombinantbaculovirus was added to the expresSF+® cells and cultured for 72 hours,then, the cells were recovered by centrifugation and preserved underfreezing at −80° C. The cells preserved under freezing were melted inice, then, suspending in a buffer (200 mM Sucrose, 1 mM EDTA, 100 mMTris-HCl (pH 7.4)) to which Complete Protease Inhibitor (Roche) had beenadded, and subjected to sonication. Thereafter, microsome fraction wasobtained according to the usual method, and preserved as DGAT1 highlyexpressed-microsome under freezing at −80° C.

(3) Measurement of DGAT1 Inhibitory Activity

As a buffer to be used in the enzymatic reaction of DGAT1, 100 mMTris-HCl (pH 7.4), 200 mM Sucrose, 20 mM MgCl₂, 0.125% Bovine SerumAlbumin (BSA) were used. To the buffer were added Test compound with apredetermined concentration as well as 15 μM dioleoylglycerol, 5 μm[¹⁴C]-palmitoyl-CoA, 100 μg protein/mL DGAT1 highly expressed-expresSF+®microsome, 0.75% acetone, and 1% dimethylsulfoxide, and triglyceride(TG) synthetic reaction was carried out at 30° C. for 20 minutes with avolume of 100 μL. 90 μL of the reaction solution was added to 810 μL ofmethanol to stop the reaction. The reaction solution was added to Oasis®μElution plate (available from Waters Corporation), and eluted with 150μL of a mixed solution of acetonitrile:isopropanol (=2:3). To elute wasadded 150 μL of MicroScinti™-40 (available from PerkinElmer Inc.), andafter thoroughly stirring the mixture, a [¹⁴C]-TG amount formed by thereaction was quantitated by measuring the same using TopCount™-NXT(available from PerkinElmer Inc.).

The inhibition rate was calculated by the following equation.

Inhibition rate (%)=(1−(TG amount at the time of adding Testcompound−Blank TG amount)÷(Control TG amount−Blank TG mount))×100

Here, a count of the [¹⁴C]-TG in the solution in which the reaction hadbeen carried out without adding Test compound is made “Control TGamount” and a count of the [¹⁴C]-TG in the solution in which Testcompound and DGAT1 highly expressed-expressSF+® microsome had not beenadded is made “Blank TG amount”. In addition, a concentration of Testcompound necessary to inhibit 50% of [¹⁴C]-TG synthesis (IC₅₀ value) wascalculated by Prism 5.01 (available from GrafPad Software Co.).

<Experimental Results>

Experimental results are shown in the following Table 16.

TABLE 16 IC₅₀ IC₅₀ Test compound (nM) Test compound (nM) Product ofExample 1-3) 4.2 Product of Example 2-2) 23 Product of Example 3-3) 2.9Product of Example 4-2) 2.0 Product of Example 5-3) 24 Product ofExample 6-3) 8.9 Product of Example 7-7) 25 Product of Example 8-2) 21Product of Example 9 5.2 Product of Example 10 9.1 Product of Example 1143 Product of Example 12 14 Product of Example 13-3) 2.3 Product ofExample 14 11 Product of Example 15 12 Product of Example 16 28 Productof Example 17 3.3 Product of Example 18-2) 6.7 Product of Example 19-3)4 Product of Example 20 8.3 Product of Example 21 8.6 Product of Example22 3.1 Product of Example 23 0.76 Product of Example 24 11 Product ofExample 25 21 Product of Example 26 11 Product of Example 27 20 Productof Example 28 19 Product of Example 29 20 Product of Example 30 15Product of Example 31 16 Product of Example 32 11 Product of Example 3314 Product of Example 34 16 Product of Example 35-3) 79.7 Product ofExample 36 5.4 Product of Example 37 4.4 Product of Example 38 36Product of Example 39 0.63 Product of Example 40 3.7 Product of Example41 2.6 Product of Example 42 5.7 Product of Example 43 48 Product ofExample 44 26 Product of Example 45 2.4 Product of Example 46 11 Productof Example 47 11 Product of Example 48 14 Product of Example 49 31Product of Example 50 47 Product of Example 51 47 Product of Example 521.8 Product of Example 53 13 Product of Example 54-4) 1.5 Product ofExample 55-2) 3.8 Product of Example 56 11 Product of Example 57 16Product of Example 58-2) 17 Product of Example 59 2.4 Product of Example60-3) 11 Product of Example 61-3) 4.2 Product of Example 62-3) 0.96Product of Example 63-3) 1.2 Product of Example 64 2.7 Product ofExample 65 2 Product of Example 66 3.8 Product of Example 67 11 Productof Example 68 26 Product of Example 69 2.7 Product of Example 70 8.1Product of Example 71 13 Product of Example 72 3.1 Product of Example 732.1 Product of Example 74 21 Product of Example 75 2.2 Product ofExample 76 1.5 Product of Example 77 0.78 Product of Example 78 3.8Product of Example 79 5.8 Product of Example 80 3.1 Product of Example81 12 Product of Example 82 3.0 Product of Example 83 4.6 Product ofExample 84 2.0 Product of Example 85-4) 30 Product of Example 86-3) 21Product of Example 87-7) 32 Product of Example 88-3) 5.8 Product ofExample 89-2) 5.3 Product of Example 90 0.87 Product of Example 91 10Product of Example 92 23 Product of Example 93-3) 11 Product of Example94-3) 1.4 Product of Example 95-6) 1.7 Product of Example 96-2) 3.1Product of Example 97-5) 4.7 Product of Example 98-3) 0.75 Product ofExample 99-6) 1.6 Product of Example 100-5) 2.9 Product of Example101-3) 0.82 Product of Example 102 74 Product of Example 103 4.8 Productof Example 104 3.6 Product of Example 105 19 Product of Example 106 75Product of Example 107 1.4 Product of Example 108 1.2 Product of Example109 2.2 Product of Example 110 19 Product of Example 111 5.5 Product ofExample 112 1.3 Product of Example 113 2.3 Product of Example 114 0.7Product of Example 115 4.5 Product of Example 116 3.5 Product of Example117 3.8 Product of Example 118 8.9 Product of Example 119 4.5 Product ofExample 120 1.8 Product of Example 121 5.4 Product of Example 122 3.4Product of Example 123 3.5 Product of Example 124 2.1 Product of Example125 2.2 Product of Example 126 1.7 Product of Example 127 2.6 Product ofExample 128 64 Product of Example 129 11 Product of Example 130 83Product of Example 131 39 Product of Example 132 3.9 Product of Example133 1.6 Product of Example 134 1.5 Product of Example 135 1 Product ofExample 136 1.9 Product of Example 137 2 Product of Example 138 1.7Product of Example 139 3.5 Product of Example 140 2.1 Product of Example141 3.1 Product of Example142 7.6 Product of Example 143 11 Product ofExample 144 11 Product of Example 145 48 Product of Example 146 8.3Product of Example 147 3.5 Product of Example 148 1.7

Experimental Example 2 Triglyceride (TG) in Blood PlasmaIncrease-Inhibiting Action Due to Lipid Administration <ExperimentalMethod>

6 to 9 weeks-old male ICR mice were fasted overnight, and Test compoundsuspended in 0.2% carboxymethyl cellulose solution was orallyadministered to the mice. A lipid (Intralipos 20%, OTSUKA PHARMACEUTICALCO., LTD., 10 mL/kg) was orally administered after 30 minutes. Blood wascollected from tail vein immediately before the lipid administration,and after 2 hours from the same to obtain blood plasma. Measurement ofTG in blood plasma was carried out by using a triglyceride E Test Wako(Wako Pure Chemical Industries, Ltd.), and an increased value of TG inblood plasma by administration of the lipid was calculated. An increasedvalue of TG in blood plasma in a solvent control group was used as acontrol, and an inhibiting rate in increase of TG in blood plasma in theTest compound administered group was calculated.

<Experimental Results>

According to the above-mentioned results, the compounds of Examplesshowed blood plasma TG increase-inhibiting action at an administrationdose of 5 mg/kg shown in the following Table 17.

TABLE 17 Inhibiting Inhibiting rate of TG- rate of TG- increase inincrease blood plasma in blood plasma Test compound (5 mg/kg) Testcompound (5 mg/kg) Product of Example 1-3) 77% Product of Example 2-2)76% Product of Example 3-3) 78% Product of Example 4-2) 60% Product ofExample 5-3) 71% Product of Example 6-3) 78% Product of Example 7-7) 71%Product of Example 8-2) 46% Product of Example 9 75% Product of Example10 62% Product of Example 11 31% Product of Example 12 51% Product ofExample 13-3) 51% Product of Example 14 69% Product of Example 15 32%Product of Example 16 74% Product of Example 17 69% Product of Example18-2) 69% Product of Example 19-3) 89% Product of Example 20 74% Productof Example 21 20% Product of Example 22 76% Product of Example 23 85%Product of Example 24 33% Product of Example 25 54% Product of Example26 67% Product of Example 27 69% Product of Example 28 59% Product ofExample 29 52% Product of Example 30 60% Product of Example 31 86%Product of Example 32 71% Product of Example 33 54% Product of Example34 19% Product of Example 35-3) 54% Product of Example 36 69% Product ofExample 39 54% Product of Example 45 71% Product of Example 46 13%Product of Example 47 72% Product of Example 48 23% Product of Example49 48% Product of Example 50 21% Product of Example 52 26% Product ofExample 53 36% Product of Example 54-4) 74% Product of Example 55-2) 60%Product of Example 56 61% Product of Example 57 43% Product of Example58-2) 64% Product of Example 59 74% (Blank) (Blank) Product of Example60-3) 48% Product of Example 61-3) 68% Product of Example 62-3) 85%Product of Example 63-3) 60% Product of Example 64 60% Product ofExample 65 75% Product of Example 66 83% Product of Example 67 70%Product of Example 68 64% Product of Example 69 85% Product of Example70 67% Product of Example 71 50% Product of Example 72 85% Product ofExample 73 88% Product of Example 74 50% Product of Example 75 5%Product of Example 76 78% Product of Example 77 75% Product of Example78 61% Product of Example 79 62% Product of Example 80 41% Product ofExample 82 47% Product of Example 83 60% Product of Example 84 75%Product of Example 85-4) 69% Product of Example 86-3) 68% Product ofExample 87-7) 57% Product of Example 88-3) 65% Product of Example 89-2)52% Product of Example 90 83% Product of Example 91 51% Product ofExample 92 74% Product of Example 93-3) 67% Product of Example 94-3) 72%Product of Example 95-6) 70% Product of Example 96-2) 48% Product ofExample 97-5) 102% Product of Example 98-3) 105% Product of Example99-6) 95% Product of Example 100-5) 60% Product of Example 101-3) 71%Product of Example 103 8% Product of Example 104 67% Product of Example105 57% Product of Example 107 62% Product of Example 108 52% Product ofExample 109 50% Product of Example 111 41% Product of Example 112 67%Product of Example 114 64% Product of Example 115 50% Product of Example116 82% Product of Example 117 57% Product of Example 118 64% Product ofExample 119 67% Product of Example 121 53% Product of Example 124 98%Product of Example 127 44% Product of Example 129 16% Product of Example131 57% Product of Example 132 65% Product of Example 133 75% Product ofExample 134 84% Product of Example 136 64% Product of Example 137 81%Product of Example 139 52% Product of Example 140 68% Product of Example141 82% Product of Example 143 55% Product of Example 144 7% Product ofExample 145 43% (Blank) (Blank)

Experimental Example 3 Antifeeding Activity <Experimental Method>

7 to 10 weeks-old male C57BL/6J mice were fasted overnight, and the testcompound suspended in 0.2% carboxymethylcellulose solution was orallyadministered. Immediately after the administration, high fat diet(Oriental Yeast Co., Ltd, 60 cal % fat) was provided and freely fed. Anamount of food ingested up to 4 hours was measured, and a lowering rate(an antifeeding rate) of the amount of food ingested in the Testcompound administered group was calculated as compared to that of thesolvent control group as a control.

<Experimental Results>

According to the above-mentioned results, the compounds of Examplesshowed antifeeding rates shown in the following Table 18 with anadministration dose of 5 mg/kg.

TABLE 18 Antifeeding Antifeeding Test compound rate (5 mg/kg) Testcompound rate (5 mg/kg) Product of Example 1-3) 77% Product of Example2-2) 64% Product of Example 3-3) 76% Product of Example 4-2) 82% Productof Example 5-3) 37% Product of Example 6-3) 71% Product of Example 7-7)75% Product of Example 8-2) 57% Product of Example 9 76% Product ofExample 10 62% Product of Example 12 40% Product of Example 13-3) 60%Product of Example 14 66% Product of Example 16 75% Product of Example17 82% Product of Example 18-2) 83% Product of Example 19-3) 78% Productof Example 20 70% Product of Example 22 69% Product of Example 23 63%Product of Example 25 81% Product of Example 26 79% Product of Example27 66% Product of Example 28 54% Product of Example 29 28% Product ofExample 30 68% Product of Example 31 65% Product of Example 32 42%Product of Example 33 44% Product of Example 35-3) 56% Product ofExample 36 63% Product of Example 39 76% Product of Example 45 72%Product of Example 47 44% Product of Example 49 58% (Blank) (Blank)Product of Example 54-4) 46% Product of Example 55-2) 39% Product ofExample 56 76% Product of Example 58-2) 65% Product of Example 59 50%Product of Example 60-3) 59% Product of Example 61-3) 80% Product ofExample 62-3) 63% Product of Example 63-3) 83% Product of Example 64 78%Product of Example 65 79% Product of Example 66 76% Product of Example67 58% Product of Example 68 63% Product of Example 69 87% Product ofExample 70 59% Product of Example 71 29% Product of Example 72 65%Product of Example 73 82% Product of Example 74 60% Product of Example76 61% Product of Example 77 65% Product of Example 78 62% Product ofExample 79 74% Product of Example 82 42% Product of Example 83 49%Product of Example 84 64% Product of Example 85-4) 70% Product ofExample 86-3) 21% Product of Example 87-7) 59% Product of Example 88-3)55% Product of Example 89-2) 75% Product of Example 90 75% Product ofExample 91 51% Product of Example 92 66% Product of Example 93-3) 68%Product of Example 94-3) 66% Product of Example 95-6) 83% Product ofExample 96-2) 58% Product of Example 97-5) 92% Product of Example 98-3)89% Product of Example 99-6) 85% Product of Example 101-3) 57% Productof Example 104 62% Product of Example 105 58% Product of Example 107 57%Product of Example 108 62% Product of Example 109 41% Product of Example112 52% Product of Example 114 59% Product of Example 115 62% Product ofExample 116 76% Product of Example 117 55% Product of Example 118 61%Product of Example 119 51% Product of Example 121 57% Product of Example124 75% Product of Example 132 47% Product of Example 133 83% Product ofExample 134 74% Product of Example 136 62% Product of Example 137 83%Product of Example 140 78% Product of Example 141 55% Product of Example143 4% (Blank) (Blank)

Experimental Example 4 Weight Gain-Inhibiting Action, HypoglycemicEffect, Insulin in Blood Plasma Lowering Action in KK-Ay Mice<Experimental Method>

To 8 weeks-old male KK-Ay mice were provided high fat diet (OrientalYeast Co., Ltd, 60 cal % fat), and Test compound suspended in 0.2%carboxymethylcellulose solution was orally administered once a day. Oraladministration was continued for 2 weeks, and a weight gain-inhibitingrate of the Test compound was calculated by using a weight gain amountof the solvent control group during the test period as 100%. After finaladministration, the mice were fasted overnight, and blood was collectedfrom tail vein. Measurement of a blood-sugar level was carried out byusing glucose Ca Test Wako (Wako Pure Chemical Industries, Ltd.), andmeasurement of insulin in blood plasma was carried out by using a mouseinsulin measurement kit (Morinaga Institute of Biological Science,Inc.).

<Experimental Results>

According to the above-mentioned results, the compounds of Examplesshowed a hypoglycemic action, insulin in blood plasma-lowering actionand weight gain-inhibiting action shown in the following table with anadministration dose of 30 mg/kg/day.

TABLE 19 Insulin in Weight blood plasma- gain- Hypoglycemic loweringinhibiting action action action (30 mg/ (30 mg/ (30 mg/ Test compoundkg/day) kg/day) kg/day) Product of Example 43% 58% 67% 1-3) Product ofExample 64% 62% 53% 2-3) Product of Example 41% 51% 52% 3-3) Product ofExample 50% 52% 49% 4-2) Product of Example 55% 56% 48% 5-3) Product ofExample 63% 72% 72% 6-3) Product of Example 62% 58% 66% 7-7) Product ofExample 23% 27% 17% 14 Product of Example 40% 47% 30% 22 Product ofExample −13%  14% 39% 23 Product of Example 40% 27% 44% 26 Product ofExample 42% 41% 39% 33 Product of Example 23% 19% 59% 36 Product ofExample 44% 50% 38% 39 Product of Example 59% 56% 42% 45 Product ofExample 74% 93% 113%  54-4) Product of Example 60% 77% 90% 61-3) Productof Example 80% 95% 161%  62-3) Product of Example 77% 90% 115%  63-3)Product of Example 10% 38% 46% 66 Product of Example  61%^(#)  37%^(#) 43%^(#) 69 Product of Example 52% 27% 45% 70 Product of Example 38% 28%43% 72 Product of Example 40% 69% 62% 73 Product of Example 56% 51% 47%74 Product of Example 65% 81% 69% 76 Product of Example 60% 65% 60% 77Product of Example 44% 49% 54% 78 Product of Example 44% 33% 42% 83Product of Example 65% 76% 48% 84 Product of Example 35% 19% 22% 87-7)Product of Example 68% 88% 63% 89-2) Product of Example 63% 58% 60% 92Product of Example  42%*  29%*  35%* 94-3) Product of Example 66% 58%75% 95-6) Product of Example 66% 71% 75% 96-2) Product of Example 57%58% 48% 107 Product of Example 49% 61% 47% 112 Product of Example 48%60% 45% 114 Product of Example 36% 35% 31% 117 Product of Example 40%28% 36% 119 ^(#)Value of an administration dose of 10 mg/kg/day *Valueof an administration dose of 1 mg/kg/day

INDUSTRIAL APPLICABILITY

The continuous arycyclic compound (I) or a pharmaceutically acceptablesalt thereof of the present invention has excellent DGAT1 inhibitoryactivity, and can be used as a prophylaxis or treatment agent ofdiabetes.

1. A continuous arycyclic compound represented by the formula:

wherein Alk represents a linear C₁₋₆ alkylene group, a branched C₁₋₆alkylene group or a C₁₋₆ alkylene group having a ring structure; where apart of the carbon atoms constituting the ring structure may beoptionally substituted by an oxygen atom, a nitrogen atom or a sulfuratom, in Ring X, X¹ represents N or CR^(X1), X² represents N or CR^(X2),X³ represents N or CR^(X3), X⁴ represents N or CR^(X4), where R^(X1),R^(X2), R^(X3) and R^(X4) each independently represents a hydrogen atom;a linear or branched C₁₋₆ alkyl group which may be substituted by ahalogen atom(s); a C₃₋₇ alkyl group having a ring structure which may besubstituted by a halogen atom(s); a linear or branched C₁₋₆ alkoxygroup; a halogen atom or a cyano group, in Ring Y, Y¹ represents N orCR^(Y1), Y² represents N or CR^(Y2), Y³ represents N or CR^(Y3), Y⁴represents N or CR^(Y4), R^(Y1), R^(Y2), R^(Y3) and R^(Y4) eachindependently represents a hydrogen atom; a linear or branched C₁₋₆alkyl group which may be substituted by a halogen atom(s); a C₃₋₇ alkylgroup having a ring structure which may be substituted by a halogenatom(s); a linear or branched C₁₋₆ alkoxy group; a halogen atom or acyano group, in Ring Z, R^(Z) represents a linear or branched C₁₋₆ alkylgroup which may be substituted by a halogen atom(s) or C₃₋₇ alkyl grouphaving a ring structure which may be substituted by a halogen atom(s),or a pharmaceutically acceptable salt thereof, provided that Ring X isneither phenyl nor pyridyl group when Ring Y is phenyl or pyridyl group.2. The continuous arycyclic compound or a pharmaceutically acceptablesalt thereof according to claim 1, wherein Ring X has a structurerepresented by any one of the following formulae:

wherein R^(X1) to R^(X4) have the same meanings as defined in claim 1,and Ring Y has a structure represented by any one of the followingformulae:

wherein R^(Y1) to R^(Y4) have the same meanings as defined in claim 1.3. The continuous arycyclic compound or a pharmaceutically acceptablesalt thereof according to claim 2, wherein Ring X has a structurerepresented by any one of the following formulae:

wherein R^(X1) to R^(X4) have the same meanings as defined in claim 1,and Ring Y has a structure represented by any one of the followingformulae:

wherein R^(Y1) to R^(Y4) have the same meanings as defined in claim 1.4. The continuous arycyclic compound or a pharmaceutically acceptablesalt thereof according to claim 3, wherein R^(Z) is a linear or branchedC₁₋₆ alkyl group which is substituted by a halogen atom(s) or a C₃₋₇alkyl group having a ring structure which may be substituted by ahalogen atom(s).
 5. The continuous arycyclic compound or apharmaceutically acceptable salt thereof according to claim 3, whereinAlk is a branched C₂₋₄ alkylene group.
 6. A continuous arycycliccompound which is any one of the following compounds:2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)-propanoicacid;2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)-oxy]propanoicacid; and2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoicacid, or a pharmaceutically acceptable salt thereof.
 7. An acyl coenzymeA: diacylglycerol acyltransferase DGAT1 inhibitor comprising thecontinuous arycyclic compound or a pharmaceutically acceptable saltthereof according to claim 1 as an effective ingredient.
 8. The DGAT1inhibitor according to claim 7 which is a prophylactic or treatmentagent of obesity.
 9. The DGAT1 inhibitor according to claim 8 which is aprophylactic or treatment agent of hyperlipidemia, hypertriglyceridemia,lipid metabolism disorder or fatty liver.
 10. The DGAT1 inhibitoraccording to claim 7 which is a prophylactic or treatment agent of type2 diabetes, diabetic complication (including diabetic peripheralneuropathy, diabetic nephropathy, diabetic retinopathy and diabeticmacrovascular disease), arteriosclerosis, hypertension, cerebrovasculardisease, coronary heart disease, dyspnoea, lumbago or kneeosteoarthritis.
 11. The DGAT1 inhibitor according to claim 10 which is aprophylactic or treatment agent of type 2 diabetes or diabeticcomplication.
 12. (canceled)
 13. A prophylaxis or treatment method ofhyperlipidemia, hypertriglyceridemia, lipid metabolism disorder, fattyliver; type 2 diabetes, diabetic complication (including diabeticperipheral neuropathy, diabetic nephropathy, diabetic retinopathy anddiabetic macrovascular disease), arteriosclerosis, hypertension,cerebrovascular disease, coronary heart disease, dyspnoea, lumbago orknee osteoarthritis which comprises administering therapeuticallyeffective amount of the continuous arycyclic compound or thepharmaceutically acceptable salt thereof according to claim 1 to apatient.
 14. The continuous arycyclic compound or a pharmaceuticallyacceptable salt thereof according to claim 4, wherein R^(z) is methylwhich is substituted by a halogen atom(s).
 15. The continuous arycycliccompound or a pharmaceutically acceptable salt thereof according toclaim 5, wherein Alk is —C(CH₃)₂—.